Carboxamide compounds and uses thereof

ABSTRACT

Disclosed are compounds of Formula (I′) methods of using the compounds for inhibiting HPK1 activity and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders associated with HPK1 activity such as cancer.

FIELD OF THE INVENTION

The disclosure provides compounds as well as their compositions andmethods of use. The compounds modulate hematopoietic progenitor kinase 1(HPK1) activity and are useful in the treatment of various diseasesincluding cancer.

BACKGROUND OF THE INVENTION

Hematopoietic progenitor kinase 1 (HPK1) originally cloned fromhematopoietic progenitor cells is a member of MAP kinase kinase kinasekinases (MAP4Ks) family, which includes MAP4K1/IPK1, MAP4K2/GCK,MAP4K3/GLK, MAP4K4/HGK, MAP4K5/KHS, and MAP4K6/MINK (Hu, M. C., et al.,Genes Dev, 1996. 10(18): p. 2251-64). HPK1 is of particular interestbecause it is predominantly expressed in hematopoietic cells such as Tcells, B cells, macrophages, dendritic cells, neutrophils, and mastcells (Hu, M. C., et al., Genes Dev, 1996. 10(18): p. 2251-64; Kiefer,F., et al., EMBO J, 1996. 15(24): p. 7013-25). HPK1 kinase activity hasbeen shown to be induced upon activation of T cell receptors (TCR)(Liou, J., et al., Immunity, 2000. 12(4): p. 399-408), B cell receptors(BCR) (Liou, J., et al., Immunity, 2000. 12(4): p. 399-408),transforming growth factor receptor (TGF-βR) (Wang, W., et al., J BiolChem, 1997. 272(36): p. 22771-5; Zhou, G., et al., J Biol Chem, 1999.274(19): p. 13133-8), or G_(s)-coupled PGE2 receptors (EP2 and EP4)(Ikegami, R., et al., J Immunol, 2001. 166(7): p. 4689-96). As such,HPK1 regulates diverse functions of various immune cells.

HPK1 is important in regulating the functions of various immune cellsand it has been implicated in autoimmune diseases and anti-tumorimmunity (Shui, J. W., et al., Nat Immunol, 2007. 8(1): p. 84-91; Wang,X., et al., J Biol Chem, 2012. 287(14): p. 11037-48). HPK1 knockout micewere more susceptible to the induction of experimental autoimmuneencephalomyelitis (EAE) (Shui, J. W., et al., Nat Immunol, 2007. 8(1):p. 84-91). In human, HPK1 was downregulated in peripheral bloodmononuclear cells of psoriatic arthritis patients or T cells of systemiclupus erythematosus (SLE) patients (Batliwalla, F. M., et al., Mol Med,2005. 11(1-12): p. 21-9). Those observations suggested that attenuationof HPK1 activity may contribute to autoimmunity in patients.Furthermore, HPK1 may also control anti-tumor immunity via Tcell-dependent mechanisms. In the PGE2-producing Lewis lung carcinomatumor model, the tumors developed more slowly in HPK1 knockout mice ascompared to wild-type mice (see US 2007/0087988). In addition, it wasshown that adoptive transfer of HPK1 deficient T cells was moreeffective in controlling tumor growth and metastasis than wild-type Tcells (Alzabin, S., et al., Cancer Immunol Immunother, 2010. 59(3): p.419-29). Similarly, BMDCs from HPK1 knockout mice were more efficient tomount a T cell response to eradicate Lewis lung carcinoma as compared towild-type BMDCs (Alzabin, S., et al., J Immunol, 2009. 182(10): p.6187-94). These data, in conjunction with the restricted expression ofHPK1 in hematopoietic cells and lack of effect on the normal developmentof immune cells, suggest that HPK1 is a drug target for enhancingantitumor immunity. Accordingly, there is a need for new compounds thatmodulate HPK1 activity.

SUMMARY

The present disclosure provides, inter alia, a compound of Formula (I′):

or a pharmaceutically acceptable salt thereof, wherein constituentvariables are defined herein.

The present disclosure further provides a pharmaceutical compositioncomprising a compound of the disclosure, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient.

The present disclosure further provides methods of inhibiting HPK1activity, which comprises administering to an individual a compound ofthe disclosure, or a pharmaceutically acceptable salt thereof. Thepresent disclosure also provides uses of the compounds described hereinin the manufacture of a medicament for use in therapy. The presentdisclosure also provides the compounds described herein for use intherapy.

The present disclosure further provides methods of treating a disease ordisorder in a patient comprising administering to the patient atherapeutically effective amount of a compound of the disclosure, or apharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

Compounds

The present disclosure provides a compound of Formula (I′):

or a pharmaceutically acceptable salt thereof, wherein:

Cy^(A) is C₃₋₁₂ cycloalkyl or 4-12 membered heterocycloalkyl; whereinthe 4-12 membered heterocycloalkyl has at least one ring-forming carbonatom and 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom N, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of the 4-12 membered heterocycloalkyl isoptionally substituted by oxo to form a carbonyl group; and wherein theC₃₋₁₂ cycloalkyl and 4-12 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR^(A);

A is N or CR¹⁶;

R¹⁶ is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, CN, NO₂, OR^(a16), SR^(a16), C(O)R^(b),C(O)NR^(c16)R^(a1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c16)R^(d16),NR^(c16)R^(d16) NR^(c16)C(O)R^(b6), NR⁶C(O)OR^(a16)NR^(c16)C(O)NR^(c16)R^(d), NR^(c16)S(O)R^(b16), NR^(c16)S(O)₂R^(b16)NR^(c16)S(O)₂NR^(c16)R^(d16), S(O)R^(b16), S(O)NR^(c16)R^(d16),S(O)₂R^(b16), S(O)₂NR^(c16)R^(d16) and BR^(h16)R¹⁶; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

R¹ is selected from H, D, halo, CN, C₁₋₆ alkyl, OR^(a15) andNR^(c15)R^(d15); wherein the C₁₋₆ alkyl is optionally substituted with1, 2, or 3 substituents independently selected from R^(g); R² isselected from H, D, Cy², C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, CN, NO₂, OR^(a), SR^(a), C(O)R, C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), C(═NR^(c))R^(b),C(═NOR^(a))R^(b), C(═NR^(c))NR^(c)R^(d), NR^(c)C(═NR^(c))NR^(c)R^(d),NR^(c)S(O)R, NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), S(O)₂NR^(c)R^(d) and BR^(h)R^(i); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹⁰;

Cy² is selected from C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl each has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰;

Z is N or CR³;

R³ is selected from H, D, Cy³, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4) NR⁴C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4), C(═NOR^(a4))R^(b4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4) NR⁴S(O)R⁴,NR⁴S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4) and BR^(h4)R^(i4);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³;

Cy³ is selected from C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl each has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹³;

each R⁴ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a8), SR^(a8), C(O)R, C(O)NR^(c8)R^(d8), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c)C(O)OR^(a8), NR^(c)C(O)NR^(c8)R^(d8), C(═NR^(c8))R^(b8),C(═NOR^(a8))R^(b8), C(═NR^(c8))NR^(c8)R^(d8),NR^(c8)C(═NR^(c8))NR^(c8)R^(d8), NR^(c)S(O)R₂NR^(c)S(O)₂R^(b8),NR^(c8)S(O)₂NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8), S(O)₂R,S(O)₂NR^(c8)R^(d8) and BR^(h8)R^(i8); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkyleneand 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁵;

-   -   each R⁵ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃        alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered        heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a9), SR^(ag),        C(O)R^(b9), C(O)NR^(c9)R^(d9), C(O)OR^(a9), NR^(c9)R^(d9),        NR^(c9)C(O)R^(b9), NR^(c9)C(O)OR^(a9), NR^(c9)S(O)R^(b9),        NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9),        S(O)NR^(c9)R^(d9), S(O)₂R^(b9), S(O)₂NR^(c9)R^(d9) and        BR^(h9)R^(i9); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,        4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R⁶;

each R⁶ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a10),SR^(a10), C(O)R^(b10), C(O)NR^(c10)R^(d10), C(O)OR^(a10),NR^(c10)R^(d10), NR^(c10)C(O)R^(b10), NR^(c10)C(O)OR^(a10)NR^(c10)(O)R^(b10), NR^(c10)(O)₂R^(b10), NR^(c10)S(O)₂NR^(c10)R^(d10),S(O)R^(b10), S(O)NR^(c10)R^(d10), S(O)₂R^(b10), andS(O)₂NR^(c10)R^(d10); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g);

each R^(A) is selected from H, D, Cy¹, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(a11), SR^(a11), C(O)R^(b11),C(O)NR^(c11)R^(d11), C(O)OR^(a11), OC(O)R^(b11), OC(O)NR^(c11)R^(d11),NR^(c11)R^(d11), NR^(c11)C(O)R^(b11), NR^(c11)C(O)OR^(a11),NR^(c11)C(O)NR^(c11)R^(d11), C(═NR^(e11))R^(b11), C(═NOR^(a11))R^(b11),C(═NR^(e11))NR^(c11)R^(d11), NR^(c11)C(═NR^(e11))NR^(c11)R^(d11),NR^(c11)S(O)R^(b11), NR^(c11)S(O)₂R^(b11), NR^(c11)S(O)₂NR^(c11)R^(d11),S(O)R^(b11), S(O)NR^(c11)R^(d11), S(O)₂R^(d11), S(O)₂NR^(c11)R^(d11) andBR^(h11)R^(i11); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁷;

Cy¹ is selected from C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl each has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R⁷;

each R⁷ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a12), SR^(a12), C(O)R^(b12), C(O)NR^(c12)R^(d12),C(O)OR^(a12), OC(O)R^(b12), OC(O)NR^(c12)R^(d12), NR^(c12)R^(d12),NR^(c12)C(O)R^(d12) NR^(e12)C(O)OR^(a12) NR^(c12)C(O)NR^(c12)R^(d12),C(═NR^(e12))R^(b12), C(═NOR^(a12))R², C(═NR^(e12))NR^(c12)R^(d12)NR^(c12)C(═NR^(e12))NR^(c12)R^(d12)NR^(c12)S(O)R^(b12),NR^(c12)S(O)₂R^(b12), NR^(c12)S(O)₂NR^(c12)R^(d12) S(O)R^(b12),S(O)NR^(c12)R^(d12), S(O)₂R^(b12), S(O)₂NR^(c12)R^(d12) andBR^(h12)R^(i12); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R;

-   -   each R⁸ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃        alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered        heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a13), SR^(a13),        C(O)R^(b13), C(O)NR^(c13)R^(d13), C(O)OR^(a13), NR^(c13)R^(d13),        NR^(c13)C(O)R^(b13), NR^(c13)C(O)OR^(a13), NR^(c13)S(O)R^(b13),        NR^(c13)S(O)₂R^(b13), NR¹³S(O)₂NR^(c13)R^(d13), S(O)R^(b13),        S(O)NR^(c13)R^(d13), S(O)₂R^(b13) S(O)₂NR^(c13)R^(d13) and        BR^(h13)R^(i13); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃        alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀        aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene        are each optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R⁹;

each R⁹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a14),SR^(a14), C(O)R^(b14), C(O)NR^(c14)R^(d14), C(O)OR^(a14),NR^(c14)R^(d14), NR^(c14)C(O)R^(b14), NR^(c14)C(O)OR^(a14),NR^(c14)S(O)R^(b14), NR^(c14)S(O)₂R^(b14), NR^(c14)S(O)₂NR^(c14)R^(d14),S(O)R^(b14), S(O)NR^(c14)R^(d14), S(O)₂R^(b14) and S(O)₂NR^(c14)R^(d14);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl,C₆₋₁₀aryl, 5-10 membered heteroaryl and 4-7 membered heterocycloalkylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g);

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),C(═NR^(e1))R^(b1), C(═NOR^(a1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),S(O)₂NR^(c1)R^(d1) and BR^(h1)R^(a); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkyleneand 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2) S(O)₂NR^(c2)R^(d2) and BR^(h2)R^(i2);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a3),SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3) and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R¹³ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5),C(═NR^(e5))R^(b5), C(═NOR^(a5))R^(b5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),S(O)₂NR^(c5)R^(d5) and BR^(h5)R^(i5); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkyleneand 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹⁴;

each R¹⁴ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)S(O)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6) S(O)₂NR^(c6)R^(d6) and BR^(h6)R^(i6);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁵;

each R¹⁵ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a7),SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), NR^(c7)R^(d7),NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7), NR^(c7)S(O)R^(b7),NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7),S(O)NR^(c7)R^(d7), S(O)₂R^(b7) and S(O)₂NR^(c7)R^(d7); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀aryl, 5-10membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R^(a), R^(c) and R^(d) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰;

or any R^(c) and R^(d) attached to the same N atom, together with the Natom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹⁰;

each R^(b) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

each R^(e) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(h) and R^(i) is independently selected from OH and C₁₋₆ alkoxy;

or any R^(h) and R^(i) attached to the same B atom are C₂₋₃ dialkoxy andtogether with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

each R^(e1) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(h1) and R^(i1) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h1) and R^(i1) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a2), R^(c2) and R^(d2) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹²;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹²;

each R^(h2) and R^(i2) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h2) and R^(i2) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a3), R^(c3) and R^(d3) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a4), R^(c4) and R^(d4) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³;

or any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹³;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³;

each R^(e4) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(h4) and R¹⁴ is independently selected from OH and C₁₋₆ alkoxy;

or any R^(h4) and R¹⁴ attached to the same B atom are C₂₋₃ dialkoxy andtogether with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a5), R^(c5) and R^(d5) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁴;

or any R^(c5) and R^(d5) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹⁴;

each R^(b5) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁴;

each R^(e5) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(h5) and R^(i5) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h5) and R^(i5) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a6), R^(c6) and R^(d6) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁵;

or any R^(c6) and R^(d6) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹⁵;

each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁵;

each R^(h6) and R^(i6) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h6) and R^(i6) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a7), R^(c7) and R^(d7) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b7) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a8), R^(c8) and R^(d8) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁵;

or any R^(c8) and R^(d8) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R⁵;

each R^(b8) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁵;

each R^(e8) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(h8) and R^(i8) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h8) and R^(i8) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a9), R^(c9) and R^(d9) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁶;

or any R^(c9) and R^(d9) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R⁶;

each R^(b9) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁶;

each R^(h9) and R^(i9) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h9) and R^(i9) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a10), R^(c10) and R^(d10) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b10) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a11), R^(c11) and R^(d11) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁷;

or any R^(c11) and R^(d11) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R⁷;

each R^(b11) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁷;

each R^(e11) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(h11) and R^(i11) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h11) and R^(i11) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a12), R^(c12) and R^(d12) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁸;

or any R^(c12) and R^(d12) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R⁸;

each R^(b12) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁸;

each R^(e12) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkylaminosulfonyl;

each R^(h12) and R^(i12) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h12) and R^(i12) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a13), R^(c13) and R^(d13) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁹;

or any R^(c13) and R^(d13) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R⁹;

each R^(b13) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁹;

each R^(h13) and R^(i13) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h13) and R^(i13) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a14), R^(c14) and R^(d14) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b14) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a15), R^(c15) and R^(d15) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(a16), R^(c16) and R^(d16) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b16) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(h16) and R^(i16) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h16) and R^(i16) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl; and

each R^(g) is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl,cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino; and

n is 0, 1, 2, 3 or 4.

The present disclosure provides a compound of Formula (F) or apharmaceutically acceptable salt thereof, wherein:

Cy^(A) is C₃₋₁₂ cycloalkyl or 4-12 membered heterocycloalkyl; whereinthe 4-12 membered heterocycloalkyl has at least one ring-forming carbonatom and 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom N, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of the 4-12 membered heterocycloalkyl isoptionally substituted by oxo to form a carbonyl group; and wherein the€3-12 cycloalkyl and 4-12 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR^(A);

A is N or CR¹⁶;

R¹⁶ is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, CN, NO₂, OR^(a16), SR^(a16), C(O)R^(b16),C(O)NR^(c16)R^(d16), C(O)OR^(a16), OC(O)R^(b16), OC(O)NR^(c16)R^(d16),NR^(c16)R^(d16), NR^(c16)C(O)R^(b16), NR^(c16)C(O)OR^(a16),NR^(c16)C(O)NR^(c16)R^(d16), NR^(c16)S(O)R^(b16), NR^(c16)S(O)₂R^(b16),NR^(c16)S(O)₂NR^(c16)R^(d16), S(O)R^(b16), S(O)NR^(c16)R^(d16),S(O)₂R^(b16), S(O)₂NR^(c16)R^(d16) and BR^(h16)R^(i16); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g);

R¹ is selected from H, D, halo, CN, C₁₋₆ alkyl and OR^(a15); wherein theC₁₋₆ alkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from R^(g);

R² is selected from H, D, Cy², C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, halo, CN, and NO₂; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

Cy² is selected from 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10membered heteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10membered heteroaryl each has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein a ring-forming carbon atom of 5-10 membered heteroaryland 4-10 membered heterocycloalkyl is optionally substituted by oxo toform a carbonyl group; and wherein the 4-10 membered heterocycloalkyland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3 or 4 substituents independently selected from R¹⁰;

Z is N or CR³;

R³ is selected from H, D, Cy³, halo and CN;

Cy³ is 6-10 membered heteroaryl; wherein the 6-10 membered heteroaryleach has at least one ring-forming carbon atom and 1, 2, 3, or 4ring-forming heteroatoms independently selected from N, O, and S;

each R⁴ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo,D, CN and OR^(a8);

R^(A) is selected from H, D, Cy¹, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN,OR^(a11), C(O)NR^(c11)R^(d11), and NR^(c11)R^(d11); wherein said C₁₋₆alkyl, is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁷;

Cy¹ is selected from C₃₋₁₀ cycloalkyl and 5-10 membered heteroaryl;wherein the 5-10 membered heteroaryl each has at least one ring-formingcarbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independentlyselected from N, O, and S; wherein a ring-forming carbon atom of 5-10membered heteroaryl is optionally substituted by oxo to form a carbonylgroup; and wherein the C₃₋₁₀ cycloalkyl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R⁷;

each R⁷ is independently selected from C₁₋₆ alkyl, halo, D, CN, OR^(a12)and NR^(c12)R^(d12);

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, 4-10membered heterocycloalkyl, halo, D, CN, OR^(a1), C(O)NR^(c1)R^(d1) andNR^(c1)R^(d1); wherein said C₁₋₆ alkyl, and 4-10 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, D, CN and OR^(a2);

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl and C₃₋₁₀ cycloalkyl; wherein said C₁₋₆ alkyl andC₃₋₁₀ cycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(a2), R^(c2) and R^(d2) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl;

each R^(a8), R^(c8) and R^(d8) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl;

each R^(a11), R^(c11) and R^(d11) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁷;

each R^(a12), R^(c12) and R^(d12) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl;

each R^(a15), R^(c15) and R^(d15) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g);

R^(a16) is independently selected from H and C₁₋₆ alkyl;

each R^(g) is independently selected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, amino, C₁₋₆ alkylthio, C₁₋₆alkylsulfonyl; and

n is 0, 1, 2 or 3.

The present disclosure provides a compound of Formula (F) or apharmaceutically acceptable salt thereof, wherein:

Cy^(A) is 4-12 membered heterocycloalkyl; wherein the 4-12 memberedheterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3,or 4 ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of the 4-12 membered heterocycloalkylis optionally substituted by oxo to form a carbonyl group; and whereinthe 4-12 membered heterocycloalkyl are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R^(A);

A is N or CR¹⁶;

R¹⁶ is selected from H, D, C₁₋₆ alkyl, halo, CN and OR^(a16);

R¹ is selected from H, D, halo, CN, C₁₋₆ alkyl and OR^(a15); wherein theC₁₋₆ alkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from R^(g);

R² is selected from H, D, Cy², C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN;wherein said C₁₋₆ alkyl, is optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

Cy² is selected from 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10membered heteroaryl each has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein a ring-forming carbon atom of 5-10 membered heteroaryland 4-10 membered heterocycloalkyl is optionally substituted by oxo toform a carbonyl group; and wherein the 4-10 membered heterocycloalkyland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3 or 4 substituents independently selected from R¹⁰;

Z is N or CR³;

R³ is selected from H, D, Cy³, halo and CN;

Cy³ is 6-10 membered heteroaryl; wherein the 6-10 membered heteroaryleach has at least one ring-forming carbon atom and 1, 2, 3, or 4ring-forming heteroatoms independently selected from N, O, and S;

each R⁴ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo,D, CN and OR^(a8);

R^(A) is selected from H, D, Cy¹, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN,OR^(a11), C(O)NR^(c11)R^(d11), and NR^(c11)R^(d11); wherein said C₁₋₆alkyl, is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁷;

Cy¹ is selected from C₃₋₁₀ cycloalkyl and 5-10 membered heteroaryl;wherein the 5-10 membered heteroaryl each has at least one ring-formingcarbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independentlyselected from N, O, and S; wherein a ring-forming carbon atom of 5-10membered heteroaryl is optionally substituted by oxo to form a carbonylgroup; and wherein the C₃₋₁₀ cycloalkyl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R⁷;

each R⁷ is independently selected from C₁₋₆ alkyl, halo, D, CN, OR^(a12)and NR^(c12)R^(d12);

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, 4-10membered heterocycloalkyl, halo, D, CN, OR^(a1), C(O)NR^(c1)R^(d1) andNR^(c1)R^(d1); wherein said C₁₋₆ alkyl, and 4-10 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, D, CN and OR^(a2);

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl and C₃₋₁₀ cycloalkyl; wherein said C₁₋₆ alkyl andC₆₋₁₀cycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(a2), R^(c2) and R^(d2) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl;

each R^(a8), R^(c8) and R^(d8) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl;

each R^(a11), R^(c11) and R^(d11) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁷;

each R^(a12), R^(c12) and R^(d12) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl;

each R^(a15), R^(c15) and R^(d15) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g);

R^(a16) is independently selected from H and C₁₋₆ alkyl;

each R^(g) is independently selected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylthio, C₁₋₆alkylsulfonyl; and

n is 0, 1, 2 or 3.

The present disclosure provides a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Cy^(A) is C₃₋₁₂ cycloalkyl or 4-12 membered heterocycloalkyl; whereinthe 4-12 membered heterocycloalkyl has at least one ring-forming carbonatom and 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom N, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of the 4-12 membered heterocycloalkyl isoptionally substituted by oxo to form a carbonyl group; and wherein theC₃₋₁₂ cycloalkyl and 4-12 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR^(A);

A is N or CF;

R¹ is selected from H, D, halo, CN, C₁₋₆ alkyl, OR^(a15) andNR^(c15)R^(d15); wherein the C₁₋₆ alkyl is optionally substituted with1, 2, or 3 substituents independently selected from R^(g);

R² is selected from H, D, Cy², C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),C(═NR^(e))R^(b), C(═NOR^(a))R^(b), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b),NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),S(O)₂NR^(c)R^(d) and BR^(h)R^(i); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

Cy² is selected from C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl each has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰;

R³ is selected from H, D, Cy³, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4), C(═NOR^(a4))R^(b4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4) andBR^(h4)R^(i4); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³;

Cy³ is selected from C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl each has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹³;

each R⁴ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8),C(O)OR^(a8), OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8),NR^(c8)C(O)R^(b8), NR^(c8)C(O)OR^(a8), NR^(c8)C(O)NR^(c8)R^(d8),C(═NR^(e8))R^(b8), C(═NOR^(a8))R^(b8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), NR^(c8)S(O)R^(b8), NR^(c8)S(O)₂R^(b8),NR^(c8)S(O)₂NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8), S(O)₂R^(b8),S(O)₂NR^(c8)R^(d8) and BR^(h8)R^(i8); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkyleneand 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁵;

each R⁵ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a9), SR^(a9), C(O)R^(b9), C(O)NR^(c9)R^(d9), C(O)OR^(a9),NR^(c9)R^(d9), NR^(c9)C(O)R^(b9), NR^(c9)C(O)OR^(a9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9),S(O)NR^(c9)R^(d9), S(O)₂R^(b9), S(O)₂NR^(c9)R^(d9) and BR^(h9)R^(i9);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁶;

each R⁶ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a10),SR^(a10), C(O)R^(b10), C(O)NR^(c10)R^(d10), C(O)OR^(a10),NR^(c10)R^(d10), NR^(c10)C(O)R^(b10), NR^(c10)C(O)OR^(a10),NR^(c10)S(O)R^(b10), NR^(c10)S(O)₂R^(b10), NR^(c10)S(O)₂NR^(c10)R^(d10),S(O)R^(b10), S(O)NR^(c10)R^(d10), S(O)₂R^(b10), andS(O)₂NR^(c10)R^(d10); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g);

R^(A) is selected from H, D, Cy¹, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(a11), SR^(a11), C(O)R^(b11),C(O)NR^(c11)R^(d11), C(O)OR^(a11), OC(O)R^(b11), OC(O)NR^(c11)R^(d11),NR^(c11)R^(d11), NR^(c11)C(O)R^(b11), NR^(c11)C(O)OR^(a11),NR^(c11)C(O)NR^(c11)R^(d11), C(═NR^(e11))R^(b11), C(═NOR^(a11))R^(b11),C(═NR^(e11))NR^(c11)R^(d11), NR^(c11)C(═NR^(e11))NR^(c11)R^(d11),NR^(c11)S(O)R^(b11), NR^(c11)S(O)₂R^(b11), NR^(c11)S(O)₂NR^(c11)R^(d11),S(O)R^(b11), S(O)NR^(c11)R^(d11), S(O)₂R^(b11), S(O)₂NR^(c11)R^(d11) andBR^(h11)R^(i11); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁷;

Cy¹ is selected from C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl each has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the C₆₋₁₀cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R⁷;

each R⁷ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a12), SR^(a12), C(O)R^(b12), C(O)NR^(c12)R^(d12),C(O)OR^(a12), OC(O)R^(b12), OC(O)NR^(c12)R^(d12), NR^(c12)R^(d12),NR^(c12)C(O)R^(b12), NR^(c12)C(O)OR^(a12), NR^(c12)C(O)NR^(c12)R^(d12),C(═NR^(e12))R^(b12), C(═NOR^(a12))R^(b12), C(═NR^(e12))NR^(c12)R^(d12),NR^(c12)C(═NR^(e12))NR^(c12)R^(d12), NR^(c12)S(O)R^(b12),NR^(c12)S(O)₂R^(b12), NR^(c12)S(O)₂NR^(c12)R^(d12), S(O)R^(b12),S(O)NR^(c12)R^(d12), S(O)₂R^(b12), S(O)₂NR^(c12)R^(d12) andBR^(h12)R^(i12); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R⁸;

each R⁸ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a13), SR^(a13), C(O)R^(b13), C(O)NR^(c13)R^(d13),C(O)OR^(a13), NR^(c13)R^(d13), NR^(c13)C(O)R^(b13),NR^(c13)C(O)OR^(a13), NR^(c13)S(O)R^(b13), NR^(c13)S(O)₂R^(b13),NR^(c13)S(O)₂NR^(c13)R^(d13), S(O)R^(b13), S(O)NR^(c13)R^(d13),S(O)₂R^(b13) S(O)₂NR^(c13)R^(d13) and BR^(h13)R^(i13); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁹;

each R⁹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a14),SR^(a14), C(O)R^(b14), C(O)NR^(c14)R^(d14), C(O)OR^(a14),NR^(c14)R^(d14), NR^(c14)C(O)R^(b14), NR^(c14)C(O)OR^(a14),NR^(c14)S(O)R^(b14), NR^(c14)S(O)₂R^(b14), NR^(c14)S(O)₂NR^(c14)R^(d14),S(O)R^(b14), S(O)NR^(c14)R^(d14), S(O)₂R^(b14) and S(O)₂NR^(c14)R^(d14);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,C₆₋₁₀aryl, 5-10 membered heteroaryl and 4-7 membered heterocycloalkylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g);

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆—K) aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),C(═NR^(e1))R^(b1), C(═NOR^(a1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),S(O)₂NR^(c1)R^(d1) and BR^(h1)R^(i1); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkyleneand 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2) S(O)₂NR^(c2)R^(d2) and BR^(h2)R¹²;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a3),SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3) and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R¹³ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5),C(═NR^(e5))R^(b5), C(═NOR^(a5))R^(b5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),S(O)₂NR^(c5)R^(d5) and BR^(h5)R^(i5); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkyleneand 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹⁴;

each R¹⁴ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)S(O)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6) S(O)₂NR^(c6)R^(d6) and BR^(h6)R^(i6);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁵;

each R¹⁵ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a7),SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), NR^(c7)R^(d7),NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7), NR^(c7)S(O)R^(b7),NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7),S(O)NR^(c7)R^(d7), S(O)₂R^(b7) and S(O)₂NR^(c7)R^(d7); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀aryl, 5-10membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R^(a), R^(c) and R^(d) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰;

or any R^(c) and R^(d) attached to the same N atom, together with the Natom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹⁰;

each R^(b) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

each R^(e) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(h) and R^(i) is independently selected from OH and C₁₋₆ alkoxy;

or any R^(h) and R^(i) attached to the same B atom are C₂₋₃ dialkoxy andtogether with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

each R^(e1) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkylaminosulfonyl;

each R^(h1) and R^(i1) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h1) and R^(i1) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a2), R^(c2) and R^(d2) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹²;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹²;

each R^(h2) and R^(i2) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h2) and R^(i2) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a3), R^(c3) and R^(d3) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a4), R^(c4) and R^(d4) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³;

or any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹³;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³;

each R^(e4) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(h4) and R¹⁴ is independently selected from OH and C₁₋₆ alkoxy;

or any R^(h4) and R¹⁴ attached to the same B atom are C₂₋₃ dialkoxy andtogether with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a5), R^(c5) and R^(d5) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁴;

or any R^(c5) and R^(d5) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹⁴;

each R^(b5) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁴;

each R^(e5) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkylaminosulfonyl;

each R^(h5) and R^(i5) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h5) and R^(i5) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a6), R^(c6) and R^(d6) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁵;

or any R^(c6) and R^(d6) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹⁵;

each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁵;

each R^(h6) and R^(i6) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h6) and R^(i6) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a7), R^(c7) and R^(d7) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b7) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a8), R^(c8) and R^(d8) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁵;

or any R^(c8) and R^(d8) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R⁵;

each R^(b8) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁵;

each R^(e8) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(h8) and R^(i8) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h8) and R^(i8) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a9), R^(c9) and R^(d9) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁶;

or any R^(c9) and R^(d9) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R⁶;

each R^(b9) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁶;

each R^(h9) and R^(i9) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h9) and R^(i9) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a10), R^(c10) and R^(d10) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b10) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a11), R^(c11) and R^(d11) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁷;

or any R^(c11) and R^(d11) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R⁷;

each R^(b11) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁷;

each R^(e11) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(h11) and R^(i11) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h11) and R^(i11) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a12), R^(c12) and R^(d12) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁸;

or any R^(c12) and R^(d12) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R⁸;

each R^(b12) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁸;

each R^(e12) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(h12) and R^(i12) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h12) and R^(i12) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a13), R^(c13) and R^(d13) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁹;

or any R^(c13) and R^(d13) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R⁹;

each R^(b13) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁹;

each R^(h13) and R^(i13) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h13) and R^(i13) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a14), R^(c14) and R^(d14) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b14) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a15), R^(c15) and R^(d15) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(g) is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl,cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino; and

n is 0, 1, 2, 3 or 4;

provided that R⁴ is other than unsubstituted or substituted4-morpholinyl, 4-thiomorpholinyl, 1-oxido-4-thiomorpholinyl and1,1-dioxido-4-thiomorpholinyl.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein:

Cy^(A) is C₃₋₁₂ cycloalkyl or 4-12 membered heterocycloalkyl; whereinthe 4-12 membered heterocycloalkyl has at least one ring-forming carbonatom and 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom N, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of the 4-12 membered heterocycloalkyl isoptionally substituted by oxo to form a carbonyl group; and wherein theC₃₋₁₂ cycloalkyl and 4-12 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR^(A);

A is N or CF;

R¹ is selected from H, D, halo, CN, C₁₋₆ alkyl, OR^(a15) andNR^(c15)R^(d15); wherein the C₁₋₆ alkyl is optionally substituted with1, 2, or 3 substituents independently selected from R^(g);

R² is selected from H, D, Cy², C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),C(═NR^(e))R^(b), C(═NOR^(a))R^(b), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b),NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),S(O)₂NR^(c)R^(d) and BR^(h)R^(i); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

Cy² is selected from C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl each has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the C₆₋₁₀cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰;

R³ is selected from H, D, Cy³, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4), C(═NOR^(a4))R^(b4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4) andBR^(h4)R^(i4); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³;

Cy³ is selected from C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl each has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹³;

each R⁴ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8),C(O)OR^(a8), OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8),NR^(c8)C(O)R^(b8), NR^(c8)C(O)OR^(a8), NR^(c8)C(O)NR^(c8)R^(d8),C(═NR^(e8))R^(b8), C(═NOR^(a8))R^(b8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), NR^(c8)S(O)R^(b8), NR^(c8)S(O)₂R^(b8),NR^(c8)S(O)₂NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8), S(O)₂R^(b8),S(O)₂NR^(c8)R^(d8) and BR^(h8)R^(i8); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkyleneand 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁵;

each R⁵ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a9), SR^(a9), C(O)R^(b9), C(O)NR^(c9)R^(d9), C(O)OR^(a9),NR^(c9)R^(d9), NR^(c9)C(O)R^(b9), NR^(c9)C(O)OR^(a9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9),S(O)NR^(c9)R^(d9), S(O)₂R^(b9), S(O)₂NR^(c9)R^(d9) and BR^(h9)R^(i9);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁶;

each R⁶ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a10),SR^(a10), C(O)R^(b10), C(O)NR^(c10)R^(d10), C(O)OR^(a10),NR^(c10)R^(d10), NR^(c10)C(O)R^(b10), NR^(c10)C(O)OR^(a10),NR^(c10)S(O)R^(b10), NR^(c10)S(O)₂R^(b10), NR^(c10)S(O)₂NR^(c10)R^(d10),S(O)R^(b10), S(O)NR^(c10)R^(d10), S(O)₂R^(b10), andS(O)₂NR^(c10)R^(d1)°; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g);

R^(A) is selected from H, D, Cy¹, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(a11), SR^(a11), C(O)R^(b11),C(O)NR^(c11)R^(d11), C(O)OR^(a11), OC(O)R^(b11), OC(O)NR^(c11)R^(d11),NR^(c11)R^(d11), NR^(c11)C(O)R^(b11), NR^(c11)C(O)OR^(a11),NR^(c11)C(O)NR^(c11)R^(d11), C(═NR^(e11))R^(b11), C(═NOR^(a11))R^(b11),C(═NR^(e11))NR^(c11)R^(d11), NR^(c11)C(═NR^(e11))NR^(c11)R^(d11),NR^(c11)S(O)R^(b11), NR^(c11)S(O)₂R^(b11), NR^(c11)S(O)₂NR^(c11)R^(d11),S(O)R^(b11), S(O)NR^(c11)R^(d11), S(O)₂R^(b11), S(O)₂NR^(c11)R^(d11) andBR^(h11)R^(i11); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁷;

Cy¹ is selected from C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl each has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R⁷;

each R⁷ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a12), SR^(a12), C(O)R^(b12), C(O)NR^(c12)R^(d12),C(O)OR^(a12), OC(O)R^(b12), OC(O)NR^(c12)R^(d12), NR^(c12)R^(d12),NR^(c12)C(O)R^(b12), NR^(c12)C(O)OR^(a12), NR^(c12)C(O)NR^(c12)R^(d12),C(═NR^(e12))R^(b12), C(═NOR^(a12))R^(b12), C(═NR^(e12))NR^(c12)R^(d12),NR^(c12)C(═NR^(e12))NR^(c12)R^(d12), NR^(c12)S(O)R^(b12),NR^(c12)S(O)₂R^(b12), NR^(c12)S(O)₂NR^(c12)R^(d12), S(O)R^(b12),S(O)NR^(c12)R^(d12), S(O)₂R^(b12), S(O)₂NR^(c12)R^(d12) andBR^(h12)R^(i12); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R⁸;

each R⁸ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a13), SR^(a13), C(O)R^(b13), C(O)NR^(c13)R^(d13),C(O)OR^(a13), NR^(c13)R^(d13), NR^(c13)C(O)R^(b13),NR^(c13)C(O)OR^(a13), NR^(c13)S(O)R^(b13), NR^(c13)S(O)₂R^(b13),NR^(c13)S(O)₂NR^(c13)R^(d13), S(O)R^(b13), S(O)NR^(c13)R^(d13),S(O)₂R^(b13) S(O)₂NR^(c13)R^(d13) and BR^(h13)R^(i13); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁹;

each R⁹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a14),SR^(a14), C(O)R^(b14), C(O)NR^(c14)R^(d14), C(O)OR^(a14),NR^(c14)R^(d14), NR^(c14)C(O)R^(b14), NR^(c14)C(O)OR^(a14),NR^(c14)S(O)R^(b14), NR^(c14)S(O)₂R^(b14), NR^(c14)S(O)₂NR^(c14)R^(d14),S(O)R^(b14), S(O)NR^(c14)R^(d14), S(O)₂R^(b14) and S(O)₂NR^(c14)R^(d14);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl,C₆₋₁₀aryl, 5-10 membered heteroaryl and 4-7 membered heterocycloalkylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g);

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),C(═NR^(e1))R^(b1), C(═NOR^(a1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),S(O)₂NR^(c1)R^(d1) and BR^(h1)R^(a); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkyleneand 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2) S(O)₂NR^(c2)R^(d2) and BR^(h2)R^(i2);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a3),SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3) and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R¹³ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5),C(═NR^(e5))R^(b5), C(═NOR^(a5))R^(b5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),S(O)₂NR^(c5)R^(d5) and BR^(h5)R^(i5); wherein said Cue alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkyleneand 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹⁴;

each R¹⁴ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)S(O)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6) S(O)₂NR^(c6)R^(d6) and BR^(h6)R^(i6);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁵;

each R¹⁵ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a7),SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), NR^(c7)R^(d7),NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7), NR^(c7)S(O)R^(b7),NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7),S(O)NR^(c7)R^(d7), S(O)₂R^(b7) and S(O)₂NR^(c7)R^(d7); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R^(a), R^(c) and R^(d) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰;

or any R^(c) and R^(d) attached to the same N atom, together with the Natom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹⁰;

each R^(b) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

each R^(e) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(h) and R^(i) is independently selected from OH and C₁₋₆ alkoxy;

or any R^(h) and R^(i) attached to the same B atom are C₂₋₃ dialkoxy andtogether with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

each R^(e1) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(h1) and R^(i1) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h1) and R^(i1) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a2), R^(c2) and R^(d2) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹²;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹²;

each R^(h2) and R^(i2) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h2) and R^(i2) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a3), R^(c3) and R^(d3) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a4), R^(c4) and R^(d4) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³;

or any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹³;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³;

each R^(e4) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(h4) and R¹⁴ is independently selected from OH and C₁₋₆ alkoxy;

or any R^(h4) and R¹⁴ attached to the same B atom are C₂₋₃ dialkoxy andtogether with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a5), R^(c5) and R^(d5) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁴;

or any R^(c5) and R^(d5) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹⁴;

each R^(b5) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁴;

each R^(e5) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkylaminosulfonyl;

each R^(h5) and R^(i5) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h5) and R^(i5) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a6), R^(c6) and R^(d6) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁵;

or any R^(c6) and R^(d6) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹⁵;

each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁵;

each R^(h6) and R^(i6) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h6) and R^(i6) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a7), R^(c7) and R^(d7) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b7) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a8), R^(c8) and R^(d8) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁵;

or any R^(c8) and R^(d8) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R⁵;

each R^(b8) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁵;

each R^(e8) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(h8) and R^(i8) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h8) and R^(i8) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a9), R^(c9) and R^(d9) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁶;

or any R^(c9) and R^(d9) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R⁶;

each R^(b9) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁶;

each R^(h9) and R^(i9) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h9) and R^(i9) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a10), R^(c10) and R^(d10) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g); eachR^(b10) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl andC₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a11), R^(c11) and R^(d11) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁷;

or any R^(c11) and R^(d11) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R⁷;

each R^(b11) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁷;

each R^(e11) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(h11) and R^(i11) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h11) and R^(i11) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a12), R^(c12) and R^(d12) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁸;

or any R^(c12) and R^(d12) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R⁸;

each R^(b12) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁸;

each R^(e12) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(h12) and R^(i12) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h12) and R^(i12) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl;

each R^(a13), R^(c13) and R^(d13) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁹;

or any R^(c13) and R^(d13) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R⁹;

each R^(b13) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁹;

each R^(h13) and R^(i13) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h13) and R^(i13) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or4 substituents independently selected from C₁₋₆ alkyl; each R^(a14),R^(c14) and R^(d14) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl and C₁₋₆haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g);

each R^(b14) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a15), R^(c15) and R^(d15) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(g) is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl,cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino; and

n is 0, 1, 2, 3 or 4.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein

Cy^(A) is 4-12 membered heterocycloalkyl; wherein the 4-12 memberedheterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3,or 4 ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of the 4-12 membered heterocycloalkylis optionally substituted by oxo to form a carbonyl group; and whereinthe 4-12 membered heterocycloalkyl are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R^(A);

A is N;

R¹ is selected from H, D, halo, CN, C₁₋₆ alkyl and OR^(a15); wherein theC₁₋₆ alkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from R^(g);

R² is selected from H, D, Cy², C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN;wherein said C₁₋₆ alkyl, is optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

Cy² is selected from 4-10 membered heterocycloalkyl, and 5-10 memberedheteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10 memberedheteroaryl each has at least one ring-forming carbon atom and 1, 2, 3,or 4 ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of 5-10 membered heteroaryl and 4-10membered heterocycloalkyl is optionally substituted by oxo to form acarbonyl group; and wherein the 4-10 membered heterocycloalkyl and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹⁰;

R³ is selected from H, D, Cy³, halo and CN;

Cy³ is 5-10 membered heteroaryl; wherein the 5-10 membered heteroaryleach has at least one ring-forming carbon atom and 1, 2, 3, or 4ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of 5-10 membered heteroaryl isoptionally substituted by oxo to form a carbonyl group; and wherein the5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹³;

each R⁴ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo,D, CN and OR^(a8); wherein said C₁₋₆ alkyl is optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R⁵;

each R⁵ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo,D, CN, OR^(a9) and NR^(c9)R^(d9);

R^(A) is selected from H, D, Cy¹, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN,OR^(a11), C(O)NR^(c11)R^(d11), and NR^(c11)R^(d11); wherein said C₁₋₆alkyl, is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁷;

Cy¹ is 5-10 membered heteroaryl; wherein the 5-10 membered heteroaryleach has at least one ring-forming carbon atom and 1, 2, 3, or 4ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of 5-10 membered heteroaryl isoptionally substituted by oxo to form a carbonyl group; and wherein the5-10 membered heteroaryl are each optionally substituted with 1, 2, 3 or4 substituents independently selected from R⁷;

each R⁷ is independently selected from C₁₋₆ alkyl, halo, D, CN, OR^(a12)and NR^(c12)R^(d12);

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, 4-10membered heterocycloalkyl, halo, D, CN, OR^(a1), C(O)NR^(c1)R^(d1) andNR^(c1)R^(d1); wherein said C₁₋₆ alkyl, and 4-10 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, D, CN and OR^(a2);

each R¹³ is independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl and C₃₋₁₀ cycloalkyl; wherein said C₁₋₆ alkyl andC₃₋₁₀ cycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(a2), R^(c2) and R^(d2) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl;

each R^(a8), R^(c8) and R^(d8) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl;

each R^(a9), R^(c9) and R^(d9) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl;

each R^(a11), R^(c11) and R^(d11) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁷;

each R^(a12), R^(c12) and R^(d12) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl;

each R^(a15), R^(c15) and R^(d15) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g);

each R^(g) is independently selected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylthio, C₁₋₆alkylsulfonyl; and

n is 0, 1, 2 or 3.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein:

Cy^(A) is C₃₋₁₂ cycloalkyl or 4-12 membered heterocycloalkyl; whereinthe 4-12 membered heterocycloalkyl has at least one ring-forming carbonatom and 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom N, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of the 4-12 membered heterocycloalkyl isoptionally substituted by oxo to form a carbonyl group; and wherein theC₃₋₁₂ cycloalkyl and 4-12 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR^(A);

A is N or CR¹⁶;

R¹⁶ is selected from H, D, C₁₋₆ alkyl, halo, CN and OR^(a16);

R¹ is selected from H, D, halo, CN, C₁₋₆ alkyl and OR^(a15); wherein theC₁₋₆ alkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from R^(g);

R² is selected from H, D, Cy², C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN andS(O)₂R^(b); wherein said C₁₋₆ alkyl, is optionally substituted with 1,2, 3, or 4 substituents independently selected from R¹⁰;

Cy² is selected from C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl each has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the C₆₋₁₀cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰;

R³ is selected from H, D, Cy³, halo and CN;

Cy³ is 6-10 membered heteroaryl; wherein the 6-10 membered heteroaryleach has at least one ring-forming carbon atom and 1, 2, 3, or 4ring-forming heteroatoms independently selected from N, O, and S;

each R⁴ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, halo, D, CN and OR^(a8);

each R⁵ is independently selected from halo, D and CN;

R^(A) is selected from H, D, Cy¹, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN,OR^(a11), C(O)NR^(c11)R^(d11), and NR^(c11)R^(d11); wherein said C₁₋₆alkyl, is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁷;

Cy¹ is selected from C₃₋₁₀ cycloalkyl and 5-10 membered heteroaryl;wherein the 5-10 membered heteroaryl each has at least one ring-formingcarbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independentlyselected from N, O, and S; wherein a ring-forming carbon atom of 5-10membered heteroaryl is optionally substituted by oxo to form a carbonylgroup; and wherein the C₃₋₁₀ cycloalkyl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R⁷;

each R⁷ is independently selected from C₁₋₆ alkyl, halo, D, CN, OR^(a12)and NR^(c12)R^(d12);

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, 4-10membered heterocycloalkyl, halo, D, CN, OR^(a1), C(O)NR^(c1)R^(d1) andNR^(c1)R^(d1); wherein said C₁₋₆ alkyl, and 4-10 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, D, CN and OR^(a2);

each R¹³ is independently selected from C₁₋₆ alkyl;

each R^(b) is independently C₁₋₆ alkyl;

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl and C₃₋₁₀ cycloalkyl; wherein said C₁₋₆ alkyl andC₃₋₁₀ cycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(a2), R^(c2) and R^(d2) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl;

each R^(a8), R^(c8) and R^(d8) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl;

each R^(a11), R^(c11) and R^(d11) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁷;

each R^(a12), R^(c12) and R^(d12) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl;

each R^(a15), R^(c15) and R^(d15) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g);

R^(a16) is independently selected from H and C₁₋₆ alkyl;

each R^(g) is independently selected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylthio, C₁₋₆alkylsulfonyl; and

n is 0, 1, 2 or 3.

In some embodiments, Cy^(A) is 4-12 membered heterocycloalkyl; whereinthe 4-12 membered heterocycloalkyl has at least one ring-forming carbonatom and 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom N, O, and S; wherein a ring-forming carbon 5 atom of the 4-12membered heterocycloalkyl is optionally substituted by oxo to form acarbonyl group; and wherein the 4-12 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R^(A).

In some embodiments, Cy^(A) is selected from2,5-diazabicyclo[2.2.1]heptan-2-yl; 3-aminopyrrolidin-1-yl;2-(aminomethyl)pyrrolidin-1-yl; 2-(hydroxymethyl)pyrrolidin-1-yl;2-(methoxymethyl)pyrrolidin-1-yl;4-amino-2-(hydroxymethyl)pyrrolidin-1-yl;4-hydroxy-2-methylpyrrolidin-1-yl; 2-(pyridin-2-yl)pyrrolidin-1-yl;hexahydropyrrolo[3,4-b]pyrrol-1 (2H)-yl; 2-methylpiperazin-1-yl;2-(hydroxymethyl)piperazin-1-yl; 3-(hydroxymethyl)morpholino;5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl;(2-hydroxyethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl);5-(propylcarbamoyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl;4-hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl;2-(hydroxymethyl)-5-methylpiperazin-1-yl;6-(hydroxymethyl)-4,7-diazaspiro[2.5]octan-7-yl;4-amino-2-(1-hydroxycyclopropyl)pyrrolidin-1-yl;4-amino-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl;4-amino-2-(hydroxymethyl-d2)pyrrolidin-1-yl;3-(hydroxymethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl;4-amino-2-methylpiperidin-1-yl; piperidin-4-yl;4-(dimethylamino)-2-(hydroxymethyl)pyrrolidin-1-yl;2-(hydroxymethyl)-4-(isopropylamino)pyrrolidin-1-yl;4-(hydroxymethyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl;2-(hydroxymethyl)morpholino; 2-(2-((dimethylamino)methyl)morpholino;2-(cyanomethyl)morpholino;3-oxotetrahydro-3H-oxazolo[3,4-a]pyrazin-7(1H)-yl;3-(hydroxymethyl)piperazin-1-yl; 3-(methoxymethyl)azetidin-1-yl;2-(hydroxymethyl)azetidin-1-yl; 2-((dimethylamino)methyl)azetidin-1-yl;4-methylpiperazin-1-yl; and 4-(2-hydroxyethyl)piperazin-1-yl.

In some embodiments, Cy^(A) is selected from2,5-diazabicyclo[2.2.1]heptan-2-yl; 3-aminopyrrolidin-1-yl;2-(aminomethyl)pyrrolidin-1-yl; 2-(hydroxymethyl)pyrrolidin-1-yl;2-(methoxymethyl)pyrrolidin-1-yl;4-amino-2-(hydroxymethyl)pyrrolidin-1-yl;4-hydroxy-2-methylpyrrolidin-1-yl; 2-(pyridin-2-yl)pyrrolidin-1-yl;hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl; 2-methylpiperazin-1-yl;2-(hydroxymethyl)piperazin-1-yl; 3-(hydroxymethyl)morpholino;5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl;(2-hydroxyethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl);5-(propylcarbamoyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl;4-hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl;2-(hydroxymethyl)-5-methylpiperazin-1-yl;6-(hydroxymethyl)-4,7-diazaspiro[2.5]octan-7-yl;4-amino-2-(1-hydroxycyclopropyl)pyrrolidin-1-yl;4-amino-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl;4-amino-2-(hydroxymethyl-d2)pyrrolidin-1-yl;3-(hydroxymethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl; and4-amino-2-methylpiperidin-1-yl.

In some embodiments, Cy^(A) is selected from2,5-diazabicyclo[2.2.1]heptan-2-yl; 3-aminopyrrolidin-1-yl;2-(aminomethyl)pyrrolidin-1-yl; 2-(hydroxymethyl)pyrrolidin-1-yl;2-(methoxymethyl)pyrrolidin-1-yl;4-amino-2-(hydroxymethyl)pyrrolidin-1-yl;4-hydroxy-2-methylpyrrolidin-1-yl; 2-(pyridin-2-yl)pyrrolidin-1-yl;hexahydropyrrolo[3,4-b]pyrrol-1 (2H)-yl; 2-methylpiperazin-1-yl;2-(hydroxymethyl)piperazin-1-yl; 3-(hydroxymethyl)morpholino;5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl;(2-hydroxyethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl); and5-(propylcarbamoyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl.

In some embodiments, Cy^(A) is selected from4-hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl;2-(hydroxymethyl)-5-methylpiperazin-1-yl;6-(hydroxymethyl)-4,7-diazaspiro[2.5]octan-7-yl;4-amino-2-(1-hydroxycyclopropyl)pyrrolidin-1-yl;4-amino-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl;4-amino-2-(hydroxymethyl-d2)pyrrolidin-1-yl;3-(hydroxymethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl; and4-amino-2-methylpiperidin-1-yl.

In some embodiments, Cy^(A) is 4-amino-2-(hydroxymethyl)pyrrolidin-1-yl.

In some embodiments, Cy^(A) is a 5-membered heterocycloalkyl.

In some embodiments, Cy^(A) is selected from2,5-diazabicyclo[2.2.1]heptanyl, pyrrolidinyl,hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl, and piperazinyl, each of whichis optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R^(A).

In some embodiments, Cy^(A) is C₃₋₁₀ cycloalkyl, wherein the C₃₋₁₀cycloalkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from R^(A). In some embodiments, Cy^(A) isselected from cyclopentyl and cyclohexyl, wherein the cyclopentyl andcyclohexyl are optionally substituted with NH₂.

In some embodiments, A is N.

In some embodiments, A is CF.

In some embodiments, A is CR¹⁶.

In some embodiments, R¹⁶ is H, CN, or OR^(a16).

In some embodiments, R^(a16) is independently selected from H and C₁₋₆alkyl. In some embodiments, R^(a16) is methyl.

In some embodiments, R¹ is selected from H, D, halo, CN, C₁₋₆ alkyl andOR^(a15); wherein the C₁₋₆ alkyl is optionally substituted with 1, 2, or3 substituents independently selected from R^(g).

In some embodiments, R¹ is selected from H, D, F, CN, methyl,hydroxymethyl and methoxy.

In some embodiments, R¹ is H or D. In some embodiments, R¹ is H. In someembodiments, R¹ is D.

In some embodiments, R¹ is halo.

In some embodiments, R¹ is F.

In some embodiments, R¹ is OR^(a15).

In some embodiments, R¹ is methoxy.

In some embodiments, R¹ is C₁₋₆ alkyl; wherein the C₁₋₆ alkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from R^(g).

In some embodiments, R¹ is hydroxymethyl.

In some embodiments, R¹ is CN.

In come embodiments, R¹ is methyl.

In some embodiments, R² is selected from H, D, Cy², C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)OR^(a), and S(O)₂R^(b); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰.

In some embodiments, R² is selected from H, D, Cy², C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), NR^(c)R^(d), NR^(c)C(O)R^(b),and NR^(c)C(O)OR^(a); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰.

In some embodiments, R² is selected from H, D, Cy², C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, CN, and OR^(a); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹⁰.

In some embodiments, R² is selected from H, D, Cy², C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, CN; wherein said C₁₋₆ alkyl, is optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹⁰.

In some embodiments, R² is selected from H, D, Cy², C₁₋₆ alkyl, halo,and S(O)₂R^(b); wherein said C₁₋₆ alkyl is optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹⁰.

In some embodiments, R² is selected from H, D, Cy², C₁₋₆ alkyl, andhalo; wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, 3, or4 substituents independently selected from R¹⁰.

In some embodiments, R² is H or D. In some embodiments, R² is H. In someembodiments, R² is D.

In some embodiments, R² is C₁₋₆ alkyl; wherein said C₁₋₆ alkyl isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰.

In some embodiments, R² is selected from isopropyl, F, Cl, Br, andS(O)₂CH₃.

In some embodiments, R² is isopropyl.

In some embodiments, R² is halo.

In some embodiments, R² is selected from Br, Cl, and F.

In some embodiments, R² is Br.

In some embodiments, R² is S(O)₂CH₃.

In some embodiments, R² is Cy².

In some embodiments, Cy² is selected from 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein the4-10 membered heterocycloalkyl and 5-10 membered heteroaryl each has atleast one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein the N and Sare optionally oxidized; wherein a ring-forming carbon atom of 5-10membered heteroaryl and 4-10 membered heterocycloalkyl is optionallysubstituted by oxo to form a carbonyl group; and wherein the 4-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰.

In some embodiments, Cy² is selected from 4-10 memberedheterocycloalkyl, and 5-10 membered heteroaryl; wherein the 4-10membered heterocycloalkyl and 5-10 membered heteroaryl each has at leastone ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein a ring-forming carbonatom of 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl isoptionally substituted by oxo to form a carbonyl group; and wherein the4-10 membered heterocycloalkyl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰.

In some embodiments, Cy² is C₆₋₁₀ aryl optionally substituted with 1, 2,3 or 4 substituents independently selected from R¹⁰.

Cy² is selected from 1-methyl-1H-pyrazol-4-yl;6-(hydroxymethyl)pyridin-3-yl; 6-(methylcarbamoyl)pyridin-3-yl;1-methyl-6-oxo-1,6-dihydropyridin-3-yl; 2-methylpyridin-3-yl;4-methoxypyridin-3-yl; 4-cyanopyridin-3-yl;1,3,5-trimethyl-1H-pyrazol-4-yl; morpholino; azetidin-1-yl;2-(methoxymethyl)azetidin-1-yl); 3-cyanopyridin-4-yl;3-methoxypyridin-4-yl; 2-cyano-6-fluorophenyl; 3-cyanopyridin-2-yl;4-cyano-1-methyl-1H-pyrazol-5-yl; tetrahydro-2H-pyran-4-yl;5-cyano-2-(pyrrolidin-1-yl)pyridin-4-yl; and 1-cyanocyclopropyl. In someembodiments, Cy² is selected from 1-methyl-1H-pyrazol-4-yl;6-(hydroxymethyl)pyridin-3-yl; 6-(methylcarbamoyl)pyridin-3-yl;1-methyl-6-oxo-1,6-dihydropyridin-3-yl; 2-methylpyridin-3-yl;4-methoxypyridin-3-yl; 4-cyanopyridin-3-yl;1,3,5-trimethyl-1H-pyrazol-4-yl; morpholino; azetidin-1-yl;2-(methoxymethyl)azetidin-1-yl); 3-cyanopyridin-4-yl;3-methoxypyridin-4-yl; 2-cyano-6-fluorophenyl; 3-cyanopyridin-2-yl; and4-cyano-1-methyl-1H-pyrazol-5-yl.

In some embodiments, Cy² is selected from 1-methyl-1H-pyrazol-4-yl;6-(hydroxymethyl)pyridin-3-yl; 6-(methylcarbamoyl)pyridin-3-yl;1-methyl-6-oxo-1,6-dihydropyridin-3-yl; 2-methylpyridin-3-yl;4-methoxypyridin-3-yl; 4-cyanopyridin-3-yl;1,3,5-trimethyl-1H-pyrazol-4-yl; morpholino; and azetidin-1-yl.

In some embodiments, Cy² is selected from2-(methoxymethyl)azetidin-1-yl); 3-cyanopyridin-4-yl;3-methoxypyridin-4-yl; 2-cyano-6-fluorophenyl; 3-cyanopyridin-2-yl; and4-cyano-1-methyl-1H-pyrazol-5-yl.

In some embodiments, Cy² is selected from 3-cyanopyridin-4-yl;4-cyanopyridin-3-yl; and 3-cyanopyridin-2-yl. In some embodiments, Cy²is 4-cyanopyridin-3-yl.

In some embodiments, Z is N.

In some embodiments, Z is CR³.

In some embodiments, R³ is selected from H, D, Cy³, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(a4), SR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4) and BR^(h4)R¹⁴;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³.

In some embodiments, R³ is selected from H, D, Cy³, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(a4), SR^(a4),C(O)R^(b4), NR^(c4)R^(d4), and NR^(c4)C(O)R^(b4); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹³.

In some embodiments, R³ is selected from H, D, Cy³, halo and CN. In someembodiments R³ is selected from H, D, F, Br, and CN.

In some embodiments, R³ is H or D. In some embodiments, R³ is H. In someembodiments, R³ is D.

In some embodiments, R³ is halo.

In some embodiments, R³ is Br.

In some embodiments, R³ is F.

In some embodiments, R³ is CN.

In some embodiments, R³ is Cy³.

In some embodiments, Cy³ is 5-10 membered heteroaryl; wherein the 5-10membered heteroaryl each has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein a ring-forming carbon atom of 5-10 membered heteroaryl isoptionally substituted by oxo to form a carbonyl group; and wherein the5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹³.

In some embodiments, Cy³ is 6-10 membered heteroaryl; wherein the 6-10membered heteroaryl each has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein a ring-forming carbon atom of 6-10 membered heteroaryl isoptionally substituted by oxo to form a carbonyl group; and wherein the6-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹³.

In some embodiments, Cy³ is selected from pyridin-3-yl and1-methyl-1H-pyrazol-4-yl.

In some embodiments, R⁴ is independently selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂,OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)OR^(a8), NR^(c8)C(O)NR^(c8)R^(d8), C(═NR^(e8))R^(b8),C(═NOR^(a8))R^(b8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), NR^(c8)S(O)R^(b8), NR^(c8)S(O)₂R^(b8),NR^(c8)S(O)₂NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8), S(O)₂R^(b8),S(O)₂NR^(c8)R^(d8) and BR^(h8)R^(i8); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and5-10 membered heteroaryl-C₁₋₃ alkylene are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R⁵.

In some embodiments, R⁴ is independently selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN, NO₂, OR^(a8),SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), NR^(c8)R^(d8),NR^(c8)C(O)R^(b8), NR^(c8)C(O)OR^(a8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), and S(O)₂NR^(c8)R^(d8); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1 or 2substituents independently selected from R⁵.

In some embodiments, R⁴ is independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, C₆₋₁₀cycloalkyl, halo, D, CN and OR^(a8); wherein said C₁₋₆alkyl, is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁵.

In some embodiments, each R⁴ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, CN and OR^(a8); wherein said C₁₋₆ alkyl isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁵.

In some embodiments, each R⁴ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, CN, and OR^(a8).

In some embodiments, each R⁴ is independently selected from D, methyl,F, Cl, CN, methoxy, methoxy-d3, ethoxy, difluoromethoxy, andcyclopropyl.

In some embodiments, each R⁴ is independently selected from halo andOR^(a8).

In some embodiments, each R⁴ is independently selected from F andmethoxy.

In some embodiments, each R⁴ is independently selected from halo.

In some embodiments, each R⁴ is independently selected from F and Cl.

In some embodiments, each R⁴ is independently selected from F andmethyl.

In some embodiments, each R⁴ is F.

In some embodiments, R⁴ is not unsubstituted or substituted4-morpholinyl, unsubstituted or substituted 4-thiomorpholinyl,unsubstituted or substituted 1-oxido-4-thiomorpholinyl, or unsubstitutedor substituted 1,1-dioxido-4-thiomorpholinyl.

In some embodiments, each R⁵ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, CN, OR^(a9) and NR^(c9)R^(d9).

In some embodiments, each R⁵ is independently selected from F and D.

In some embodiments, each R^(A) is selected from H, D, Cy¹, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(a11),SR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11), C(O)OR^(a11), andNR^(c11)R^(d11); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁷.

In some embodiments, R^(A) is selected from H, D, Cy¹, C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, CN, OR^(a11), C(O)NR^(c11)R^(d11), and NR^(c11)R^(d11);wherein said C₁₋₆ alkyl, is optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁷.

In some embodiments, R^(A) is selected from Cy¹, C₁₋₆ alkyl, OR^(a11),C(O)NR^(c11)R^(d11), and NR^(c11)R^(d11); wherein said C₁₋₆ alkyl, isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁷.

In some embodiments, R^(A) is C₁₋₆ alkyl; wherein said C₁₋₆ alkyl, isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁷.

In some embodiments, R^(A) is selected from methyl and ethyl; whereinsaid methyl and ethyl are each optionally substituted with 1, 2, or 3substituents independently selected from R⁷.

In some embodiments, R^(A) is Cy¹.

In some embodiments, R^(A) is selected from OH, NH₂, aminomethyl,hydroxymethyl, methoxymethyl, OH, pyridinyl, ethyl, hydroxy ethyl, andpropyl carbamoyl.

In some embodiments, Cy¹ is selected from C₃₋₁₀ cycloalkyl and 5-10membered heteroaryl; wherein the 5-10 membered heteroaryl each has atleast one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein the N and Sare optionally oxidized; wherein a ring-forming carbon atom of 5-10membered heteroaryl is optionally substituted by oxo to form a carbonylgroup; and wherein the C₃₋₁₀ cycloalkyl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R⁷.

In some embodiments, Cy¹ is 5-10 membered heteroaryl; wherein the 5-10membered heteroaryl has at least one ring-forming carbon atom and 1, 2,3, or 4 ring-forming heteroatoms independently selected from N, O, andS; and wherein the 5-10 membered heteroaryl is optionally substitutedwith 1, 2, 3 or 4 substituents independently selected from R⁷.

In some embodiments, Cy¹ is selected from C₃₋₁₀ cycloalkyl optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR⁷.

In some embodiments, Cy¹ is pyridinyl. In some embodiments, Cy¹ iscyclopropyl.

In some embodiments, each R⁷ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN, NO₂, OR^(a12),SR^(a12), C(O)R^(b12), C(O)NR^(c12)R^(d12), C(O)OR^(a12), OC(O)R^(b12),and NR^(c12)R^(d12); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁸.

In some embodiments, each R⁷ is independently selected from C₁₋₆ alkyl,halo, D, CN, OR^(a12) and NR^(c12)R^(d12).

In some embodiments, each R⁷ is independently selected from CN,OR^(a12), NR^(c12)R^(d12), and D.

In some embodiments, each R⁷ is independently selected from OR^(a12), D,and NR^(c12)R^(d12).

In some embodiments, each R⁷ is independently selected from D, CN, NH₂,and methoxy.

In some embodiments, each R⁷ is independently selected from OH, D, NH₂,and methoxy.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR^(a1),C(O)NR^(c1)R^(d1) and NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, and 4-10membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, 4-10 memberedheterocycloalkyl, halo, D, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), andNR^(c1)C(O)NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, and 4-10 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,4-10 membered heterocycloalkyl, CN, OH, OR^(a1), C(O)NR^(c1)R^(d1) andNR^(c1)R^(d1); wherein said C₁₋₆ alkyl, and 4-10 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,4-10 membered heterocycloalkyl, halo, CN, OH, OR^(a1), C(O)NR^(c1)R^(d1)and NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, and 4-10 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from OH, CN,methyl, hydroxymethyl, methyl carbamoyl, methoxy, morpholino, andcyclobutylamino.

In some embodiments, each R¹⁰ is independently selected from OH, F, CN,methyl, hydroxymethyl, methyl carbamoyl, methoxy, morpholino, andcyclobutylamino.

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, CN and OR^(a2).

In some embodiments, each R¹¹ is OR^(a2). In some embodiments, each R¹¹is OH.

In some embodiments, each R¹³ is independently selected from C₁₋₆ alkyland C₁₋₆ haloalkyl.

In some embodiments, each R¹³ is independently C₁₋₆ alkyl.

In some embodiments, R¹³ is methyl.

In some embodiments, each R^(a1), R^(c1) and R^(d1) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl and C₃₋₁₀ cycloalkyl;wherein said C₁₋₆ alkyl and C₃₋₁₀ cycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹.

In some embodiments, each R^(a1), R^(c1) and R^(d1) is independentlyselected from H, C₁₋₆ alkyl, and C₃₋₁₀ cycloalkyl; wherein said C₁₋₆alkyl and C₃₋₁₀ cycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹¹.

In some embodiments, each R^(a2), R^(c2) and R^(d2) is independentlyselected from H, C₁₋₆ alkyl and C₁₋₆ haloalkyl. In some embodiments,each R^(a2), R^(c2) and R^(d2) is independently H.

In some embodiments, each R^(a8), R^(c8) and R^(d8) is independentlyselected from H, C₁₋₆ alkyl and C₁₋₆ haloalkyl. In some embodiments,each R^(a8), R^(c8) and R^(d8) is independently selected from H and C₁₋₆alkyl.

In some embodiments, each R^(a9), R^(c9) and R^(d9) is independentlyselected from H, C₁₋₆ alkyl and C₁₋₆ haloalkyl. In some embodiments,each R^(a9), R^(c9) and R^(d9) is independently selected from H and C₁₋₆alkyl.

In some embodiments, each R^(a11), R^(c11) and R^(d11) is independentlyselected from H, C₁₋₆ alkyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkylis optionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁷. In some embodiments, each R^(a11), R^(c11) and R^(d11)is independently selected from H and C₁₋₆ alkyl; wherein said C₁₋₆ alkylis optionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁷.

In some embodiments, each R^(a12), R^(c12) and R^(d12) is independentlyselected from H, C₁₋₆ alkyl and C₁₋₆ haloalkyl.

In some embodiments, R^(a12) is H.

In some embodiments, R^(c12) and R^(d12) are each H.

In some embodiments, each R^(a15), R^(c15) and R^(d15) is independentlyselected from H, C₁₋₆ alkyl and C₁₋₆haloalkyl; wherein said C₁₋₆ alkylis optionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g). In some embodiments, each R^(a15), R^(c15) andR^(d15) is independently selected from H and C₁₋₆ alkyl; wherein saidC₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g).

In some embodiments, each R^(g) is independently selected from OH, CN,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, amino,C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl. In some embodiments, each R^(g) isOH.

In some embodiments, n is 0, 1, 2, 3 or 4. In some embodiments, n is 0,1, 2, or 3. In some embodiments, n is 0. In some embodiments, n is 1. Insome embodiments, n is 2. In some embodiments, n is 3. In someembodiments, n is 4.

In some embodiments, provided herein is a compound having Formula IA:

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound having Formula IB:

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound having Formula IC:

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound having Formula IIA:

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound having Formula IIB:

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound having Formula IIC:

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound having Formula IID:

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound having Formula III:

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound having Formula IV:

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound having Formula V:

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound having Formula VI:

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound selected from:

-   N-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (S)—N-(2-(3-aminopyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (R)—N-(2-(2-(aminomethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (R)—N-(5-fluoro-2-(2-(hydroxymethyl)pyrrolidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (R)—N-(5-fluoro-2-(2-(methoxymethyl)pyrrolidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(5-fluoro-2-((2S,4S)-4-hydroxy-2-methylpyrrolidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(5-fluoro-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(5-fluoro-2-(hexahydropyrrolo[3,4-b]pyrrol-1    (2H)-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (R)—N-(5-fluoro-2-(2-methylpiperazin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (R)—N-(5-fluoro-2-(2-(hydroxymethyl)piperazin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(5-fluoro-2-(3-(hydroxymethyl)morpholino)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-bromo-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-cyanophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-3-(pyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-3-(1-methyl-1N-pyrazol-4-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-4-(hydroxymethyl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-bromo-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl)-5-fluoro-4-(6-(hydroxymethyl)pyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-4-(6-(methylcarbamoyl)pyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-4-(2-methylpyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-(2-methylpyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-(4-methoxypyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-4-morpholinophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(4-(azetidin-1-yl)-2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-4-(morpholinomethyl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl)-4-((cyclobutylamino)methyl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((1R,4R)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(5-fluoro-2-((1R,4R)-5-(2-hydroxyethyl)-2,5-diazabicyclo[2,2,1]heptan-2-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (1R,4R)-5-(4-fluoro-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)-N-propyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide;-   N-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-methoxyphenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-(hydroxymethyl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;    and-   N-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-cyanophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound selected from:

-   N-(4-(azetidin-1-yl)-2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-((S)-2-(methoxymethyl)azetidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-(3-cyanopyridin-4-yl)-3-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2R,4R)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(3-cyanopyridin-4-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(2-methylpyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(3-methoxypyridin-4-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(3-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2′-cyano-6′-fluorobiphenyl-4-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(3-cyanopyridin-2-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyano-1-methyl-1H-pyrazol-5-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-isopropyl    phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(4-(3-cyanopyridin-4-yl)-2-((2S,4S)-4-hydroxy-2-(hydroxy    methyl)pyrrolidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(4-(4-cyanopyridin-3-yl)-2-((2S,5S)-2-(hydroxymethyl)-5-methylpiperazin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(4-(4-cyanopyridin-3-yl)-2-((2S,5S)-2-(hydroxymethyl)-5-methylpiperazin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (S)—N-(4-(4-cyanopyridin-3-yl)-2-(6-(hydroxymethyl)-4,7-diazaspiro[2.5]octan-7-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-amino-2-(1-hydroxycyclopropyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-amino-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-amino-2-(hydroxymethyl-d2)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(4-(4-cyanopyridin-3-yl)-2-((1S,3S,4S)-3-(hydroxymethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(4-(4-cyanopyridin-3-yl)-2-((1S,4S)-1-(hydroxymethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-amino-2-methylpiperidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-6-(2-fluoro-6-methoxyphenyl)picolinamide;-   N-(2-(2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-5-cyano-6-(2-fluoro-6-methoxyphenyl)picolinamide;-   N-(2-(2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-6-(2-fluoro-6-methoxyphenyl)-5-methoxypicolinamide;-   N-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2,6-difluorophenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methylphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-chloro-6-fluorophenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2,6-difluorophenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(3-cyano-2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2,3-difluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-(methoxy-d3)-3-methylphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxy-4-methylphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(3,6-difluoro-2-methylphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2,3-difluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(3,6-difluoro-2-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(3-cyano-2-fluoro-6-(methoxy-d₃)phenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(3,6-difluoro-2-(methoxy-d₃)phenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2,3-difluoro-6-(methoxy-d₃)phenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-(methoxy-d₃)phenyl)pyrimidine-4-carboxamide;-   2-(2-Fluoro-6-methoxyphenyl)-N-(2-(piperidin-4-yl)phenyl)pyrimidine-4-carboxamide;-   N-(2-(cis)4-Aminocyclohexyl)phenyl)-2-(2-fluoro-6-methoxyphenyl)    pyrimidine-4-carboxamide;-   N-(2-(trans)4-Aminocyclohexyl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-(3-Aminocyclohexyl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-(3-aminocyclopentyl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((cis)-4-Aminocyclohexyl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((trans)-4-Aminocyclohexyl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((cis)-4-Aminocyclohexyl)-4-(4-cyano-1-methyl-1H-pyrazol-5-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((trans)-4-aminocyclohexyl)-4-(4-cyano-1-methyl-1N-pyrazol-5-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((cis)-4-Aminocyclohexyl)-4-(1,3,5-trimethyl-1N-pyrazol-4-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(methylsulfonyl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-methylphenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-(Dimethylamino)-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(5-Fluoro-2-((2S,4S)-2-(hydroxymethyl)-4-(isopropylamino)pyrrolidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(tetrahydro-2H-pyran-4-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-chlorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(5-cyano-2-(pyrrolidin-1-yl)pyridin-4-yl)phenyl)-2-(2,6-difluorophenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(1-cyanocyclopropyl)phenyl)-2-(2,6-difluorophenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-(difluoromethoxy)-6-fluorophenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-(methoxy-d₃)phenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-cyclopropyl-6-fluorophenyl)pyrimidine-4-carboxamide;-   N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-ethoxy-6-fluorophenyl)pyrimidine-4-carboxamide;-   N-(4-(4-Cyanopyridin-3-yl)-2-((1S,4S)-4-(hydroxymethyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (S)—N-(4-(4-Cyanopyridin-3-yl)-2-(2-(hydroxymethyl)morpholino)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (S)—N-(4-(4-Cyanopyridin-3-yl)-2-(2-((dimethylamino)methyl)morpholino)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (R)—N-(2-(2-(Cyanomethyl)morpholino)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (R)—N-(4-(4-Cyanopyridin-3-yl)-2-(3-oxotetrahydro-3H-oxazolo[3,4-a]pyrazin-7(1H)-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (S)—N-(5-Fluoro-2-(3-(hydroxymethyl)piperazin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(4-(4-Cyanopyridin-3-yl)-2-(3-(methoxymethyl)azetidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (S)—N-(4-(4-Cyanopyridin-3-yl)-2-(2-(hydroxymethyl)azetidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (R)—N-(4-(4-Cyanopyridin-3-yl)-2-(2-((dimethylamino)methyl)azetidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(4-(4-Cyanopyridin-3-yl)-2-(4-methylpiperazin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(4-(4-Cyanopyridin-3-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;    and

(S)—N-(5-Fluoro-2-(3-(hydroxymethyl)piperazin-1-yl)-4-isopropylphenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;

or a pharmaceutically acceptable salt thereof.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment (while theembodiments are intended to be combined as if written in multiplydependent form). Conversely, various features of the invention whichare, for brevity, described in the context of a single embodiment, canalso be provided separately or in any suitable subcombination. Thus, itis contemplated as features described as embodiments of the compounds ofFormula (I) and (F) can be combined in any suitable combination.

At various places in the present specification, certain features of thecompounds are disclosed in groups or in ranges. It is specificallyintended that such a disclosure include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆ alkyl” is specifically intended to individually disclose(without limitation) methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl and C₆alkyl.

The term “n-membered,” where n is an integer, typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

At various places in the present specification, variables definingdivalent linking groups may be described. It is specifically intendedthat each linking substituent include both the forward and backwardforms of the linking substituent. For example, —NR(CR′R″)_(n)— includesboth —NR(CR′R″)_(n)— and —(CR′R″)_(n)NR— and is intended to discloseeach of the forms individually. Where the structure requires a linkinggroup, the Markush variables listed for that group are understood to belinking groups. For example, if the structure requires a linking groupand the Markush group definition for that variable lists “alkyl” or“aryl” then it is understood that the “alkyl” or “aryl” represents alinking alkylene group or arylene group, respectively.

The term “substituted” means that an atom or group of atoms formallyreplaces hydrogen as a “substituent” attached to another group. The term“substituted”, unless otherwise indicated, refers to any level ofsubstitution, e.g., mono-, di-, tri-, tetra- or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.It is to be understood that substitution at a given atom is limited byvalency. It is to be understood that substitution at a given atomresults in a chemically stable molecule. The phrase “optionallysubstituted” means unsubstituted or substituted. The term “substituted”means that a hydrogen atom is removed and replaced by a substituent. Asingle divalent substituent, e.g., oxo, can replace two hydrogen atoms.

The term “C_(n-m)” indicates a range which includes the endpoints,wherein n and m are integers and indicate the number of carbons.Examples include C₁₋₄, C₁₋₆ and the like.

The term “alkyl” employed alone or in combination with other terms,refers to a saturated hydrocarbon group that may be straight-chained orbranched. The term “C_(n-m) alkyl”, refers to an alkyl group having n tom carbon atoms. An alkyl group formally corresponds to an alkane withone C—H bond replaced by the point of attachment of the alkyl group tothe remainder of the compound. In some embodiments, the alkyl groupcontains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moietiesinclude, but are not limited to, chemical groups such as methyl, ethyl,N-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higherhomologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl and the like.

The term “alkenyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more double carbon-carbon bonds. Analkenyl group formally corresponds to an alkene with one C—H bondreplaced by the point of attachment of the alkenyl group to theremainder of the compound. The term “C_(n-m) alkenyl” refers to analkenyl group having n to m carbons. In some embodiments, the alkenylmoiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenylgroups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl and the like.

The term “alkynyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more triple carbon-carbon bonds. Analkynyl group formally corresponds to an alkyne with one C—H bondreplaced by the point of attachment of the alkyl group to the remainderof the compound. The term “C_(n-m) alkynyl” refers to an alkynyl grouphaving n to m carbons. Example alkynyl groups include, but are notlimited to, ethynyl, propyn-1-yl, propyn-2-yl and the like. In someembodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3carbon atoms.

The term “alkylene”, employed alone or in combination with other terms,refers to a divalent alkyl linking group. An alkylene group formallycorresponds to an alkane with two C—H bond replaced by points ofattachment of the alkylene group to the remainder of the compound.

The term “C_(n-m) alkylene” refers to an alkylene group having n to mcarbon atoms. Examples of alkylene groups include, but are not limitedto, ethan-1,2-diyl, ethan-1,1-diyl, propan-1,3-diyl, propan-1,2-diyl,propan-1,1-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl,2-methyl-propan-1,3-diyl and the like.

The term “alkoxy”, employed alone or in combination with other terms,refers to a group of formula —O-alkyl, wherein the alkyl group is asdefined above. The term “C_(n-m) alkoxy” refers to an alkoxy group, thealkyl group of which has n to m carbons. Example alkoxy groups includemethoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms. The term “C n-m dialkoxy” refers to a linking groupof formula —O—(C_(n-m) alkyl)-O—, the alkyl group of which has n to mcarbons. Example dialkyoxy groups include —OCH₂CH₂O— and OCH₂CH₂CH₂O—.In some embodiments, the two O atoms of a C_(n-m) dialkoxy group may beattached to the same B atom to form a 5- or 6-membered heterocycloalkylgroup.

The term “amino” refers to a group of formula —NH₂.

The term “carbonyl”, employed alone or in combination with other terms,refers to a —C(═O)— group, which also may be written as C(O).

The term “cyano” or “nitrile” refers to a group of formula —C═N, whichalso may be written as —CN.

The terms “halo” or “halogen”, used alone or in combination with otherterms, refers to fluoro, chloro, bromo and iodo. In some embodiments,“halo” refers to a halogen atom selected from F, Cl, or Br. In someembodiments, halo groups are F.

The term “haloalkyl” as used herein refers to an alkyl group in whichone or more of the hydrogen atoms has been replaced by a halogen atom.The term “C_(n-m) haloalkyl” refers to a C_(n-m) alkyl group having n tom carbon atoms and from at least one up to {2(n to m)+1} halogen atoms,which may either be the same or different. In some embodiments, thehalogen atoms are fluoro atoms. In some embodiments, the haloalkyl grouphas 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF₃,C₂F₅, CHF₂, CH₂F, CCl₃, CHCl₂, C₂Cl₅ and the like. In some embodiments,the haloalkyl group is a fluoroalkyl group.

The term “haloalkoxy”, employed alone or in combination with otherterms, refers to a group of formula —O-haloalkyl, wherein the haloalkylgroup is as defined above. The term “C_(n-m) haloalkoxy” refers to ahaloalkoxy group, the haloalkyl group of which has n to m carbons.Example haloalkoxy groups include trifluoromethoxy and the like. In someembodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

The term “oxo” refers to an oxygen atom as a divalent substituent,forming a carbonyl group when attached to carbon, or attached to aheteroatom forming a sulfoxide or sulfone group, or an N-oxide group. Insome embodiments, heterocyclic groups may be optionally substituted by 1or 2 oxo (═O) substituents.

The term “sulfido” refers to a sulfur atom as a divalent substituent,forming a thiocarbonyl group (C═S) when attached to carbon.

The term “oxidized” in reference to a ring-forming N atom refers to aring-forming N-oxide.

The term “oxidized” in reference to a ring-forming S atom refers to aring-forming sulfonyl or ring-forming sulfinyl.

The term “aromatic” refers to a carbocycle or heterocycle having one ormore polyunsaturated rings having aromatic character (i.e., having(4n+2) delocalized π (pi) electrons where n is an integer).

The term “aryl,” employed alone or in combination with other terms,refers to an aromatic hydrocarbon group, which may be monocyclic orpolycyclic (e.g., having 2 fused rings). The term “C_(n-m) aryl” refersto an aryl group having from n to m ring carbon atoms. Aryl groupsinclude, e.g., phenyl, naphthyl, and the like. In some embodiments, arylgroups have from 6 to about 10 carbon atoms. In some embodiments arylgroups have 6 carbon atoms. In some embodiments aryl groups have 10carbon atoms. In some embodiments, the aryl group is phenyl. In someembodiments, the aryl group is naphthyl.

The term “heteroaryl” or “heteroaromatic,” employed alone or incombination with other terms, refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen and nitrogen. In some embodiments, the heteroarylring has 1, 2, 3 or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In some embodiments, any ring-formingN in a heteroaryl moiety can be an N-oxide. In some embodiments, theheteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3 or 4heteroatom ring members independently selected from nitrogen, sulfur andoxygen. In some embodiments, the heteroaryl has 5-10 ring atomsincluding carbon atoms and 1, 2, 3 or 4 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatomring members independently selected from nitrogen, sulfur and oxygen. Insome embodiments, the heteroaryl is a five-membered or six-memberedheteroaryl ring. In other embodiments, the heteroaryl is aneight-membered, nine-membered or ten-membered fused bicyclic heteroarylring. Example heteroaryl groups include, but are not limited to,pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, furanyl,thiophenyl, quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-,1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,6-naphthyridine),indolyl, isoindolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl,imidazo[1,2-b]thiazolyl, purinyl, and the like. In some embodiments, theheteroaryl group is pyridone (e.g., 2-pyridone).

A five-membered heteroaryl ring is a heteroaryl group having five ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary five-membered ring heteroarylsinclude thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl,pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl, and pyridazinyl.

The term “cycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic hydrocarbon ring system (monocyclic,bicyclic or polycyclic), including cyclized alkyl and alkenyl groups.The term “C_(n-m) cycloalkyl” refers to a cycloalkyl that has n to mring member carbon atoms. Cycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles.Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C₃₋₇).In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to5 ring members, or 3 to 4 ring members. In some embodiments, thecycloalkyl group is monocyclic. In some embodiments, the cycloalkylgroup is monocyclic or bicyclic. In some embodiments, the cycloalkylgroup is a C₃₋₆ monocyclic cycloalkyl group. Ring-forming carbon atomsof a cycloalkyl group can be optionally oxidized to form an oxo orsulfido group. Cycloalkyl groups also include cycloalkylidenes. In someembodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the cycloalkyl ring, e.g., benzo or thienyl derivativesof cyclopentane, cyclohexane and the like. A cycloalkyl group containinga fused aromatic ring can be attached through any ring-forming atomincluding a ring-forming atom of the fused aromatic ring. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl,bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In someembodiments, the cycloalkyl group is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

The term “heterocycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic ring or ring system, which mayoptionally contain one or more alkenylene groups as part of the ringstructure, which has at least one heteroatom ring member independentlyselected from nitrogen, sulfur, oxygen and phosphorus, and which has4-10 ring members, 4-7 ring members, or 4-6 ring members. Includedwithin the term “heterocycloalkyl” are monocyclic 4-, 5-, 6- and7-membered heterocycloalkyl groups. Heterocycloalkyl groups can includemono- or bicyclic (e.g., having two fused or bridged rings) orspirocyclic ring systems. In some embodiments, the heterocycloalkylgroup is a monocyclic group having 1, 2 or 3 heteroatoms independentlyselected from nitrogen, sulfur and oxygen. Ring-forming carbon atoms andheteroatoms of a heterocycloalkyl group can be optionally oxidized toform an oxo or sulfido group or other oxidized linkage (e.g., C(O),S(O), C(S) or S(O)₂, N-oxide etc.) or a nitrogen atom can bequaternized. The heterocycloalkyl group can be attached through aring-forming carbon atom or a ring-forming heteroatom. In someembodiments, the heterocycloalkyl group contains 0 to 3 double bonds. Insome embodiments, the heterocycloalkyl group contains 0 to 2 doublebonds. Also included in the definition of heterocycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the heterocycloalkyl ring, e.g., benzo or thienylderivatives of piperidine, morpholine, azepine, etc. A heterocycloalkylgroup containing a fused aromatic ring can be attached through anyring-forming atom including a ring-forming atom of the fused aromaticring. Examples of heterocycloalkyl groups include2,5-diazobicyclo[2.2.1]heptanyl; pyrrolidinyl;hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl; 1,6-dihydropyridinyl;morpholinyl; azetidinyl; piperazinyl; and 4,7-diazaspiro[2.5]octan-7-yl.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas an azetidin-3-ylring is attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. One method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, e.g., optically active acids,such as the D and L forms of tartaric acid, diacetyltartaric acid,dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or thevarious optically active camphorsulfonic acids such as β-camphorsulfonicacid. Other resolving agents suitable for fractional crystallizationmethods include stereoisomerically pure forms of α-methylbenzylamine(e.g., S and R forms, or diastereomerically pure forms),2-phenylglycinol, norephedrine, ephedrine, A-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

In some embodiments, the compounds of the invention have the(R)-configuration. In other embodiments, the compounds have the(S)-configuration. In compounds with more than one chiral centers, eachof the chiral centers in the compound may be independently (R) or (S),unless otherwise indicated.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone—enol pairs, amide—imidic acidpairs, lactam—lactim pairs, enamine—imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system,e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium. One ormore constituent atoms of the compounds of the invention can be replacedor substituted with isotopes of the atoms in natural or non-naturalabundance. In some embodiments, the compound includes at least onedeuterium atom. For example, one or more hydrogen atoms in a compound ofthe present disclosure can be replaced or substituted by deuterium. Insome embodiments, the compound includes two or more deuterium atoms. Insome embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11 or 12 deuterium atoms. Synthetic methods for including isotopes intoorganic compounds are known in the art (Deuterium Labeling in OrganicChemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts,1971; The Renaissance of H/D Exchange by Jens Atzrodt, Volker Derdau,Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007,7744-7765; The Organic Chemistry of Isotopic Labelling by James R.Hanson, Royal Society of Chemistry, 2011). Isotopically labeledcompounds can used in various studies such as NMR spectroscopy,metabolism experiments, and/or assays.

Substitution with heavier isotopes such as deuterium, may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements, andhence may be preferred in some circumstances. (A. Kerekes et. al. J. MedChem. 2011, 54, 201-210; R. Xu et. al. J. Label Compd Radiopharm. 2015,58, 308-312).

The term, “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers and isotopes of thestructures depicted. The term is also meant to refer to compounds of theinventions, regardless of how they are prepared, e.g., synthetically,through biological process (e.g., metabolism or enzyme conversion), or acombination thereof.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated. When in the solid state, thecompounds described herein and salts thereof may occur in various formsand may, e.g., take the form of solvates, including hydrates. Thecompounds may be in any solid state form, such as a polymorph orsolvate, so unless clearly indicated otherwise, reference in thespecification to compounds and salts thereof should be understood asencompassing any solid state form of the compound.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, e.g., a composition enriched in the compounds of the invention.

Substantial separation can include compositions containing at leastabout 50%, at least about 60%, at least about 70%, at least about 80%,at least about 90%, at least about 95%, at least about 97%, or at leastabout 99% by weight of the compounds of the invention, or salt thereof.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, e.g., a temperature from about 20°C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. The term “pharmaceutically acceptablesalts” refers to derivatives of the disclosed compounds wherein theparent compound is modified by converting an existing acid or basemoiety to its salt form. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, mineral or organic acid salts of basicresidues such as amines; alkali or organic salts of acidic residues suchas carboxylic acids; and the like. The pharmaceutically acceptable saltsof the present invention include the non-toxic salts of the parentcompound formed, e.g., from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, alcohols (e.g., methanol, ethanol,iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17^(th)Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al, J.Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al, Handbook ofPharmaceutical Salts; Properties, Selection, and Use, (Wiley, 2002). Insome embodiments, the compounds described herein include the N-oxideforms.

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes, such as those inthe Schemes below.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediatesor products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups is described, e.g., in Kocienski, Protecting Groups,(Thieme, 2007); Robertson, Protecting Group Chemistry, (OxfordUniversity Press, 2000); Smith et al., March's Advanced OrganicChemistry; Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley,2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,”J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groupsin Organic Synthesis, 4th Ed., (Wiley, 2006).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry or by chromatographic methods such as high performanceliquid chromatography (HPLC) or thin layer chromatography (TLC).

The Schemes below provide general guidance in connection with preparingthe compounds of the invention. One skilled in the art would understandthat the preparations shown in the Schemes can be modified or optimizedusing general knowledge of organic chemistry to prepare variouscompounds of the invention.

Compounds of Formula (I) and (F) can be prepared, e.g., using a processas illustrated in the schemes below.

Compounds of Formula (I) and (F) can be prepared using a process asillustrated in Scheme 1. In the process depicted in Scheme 1, the halosubstituent of compounds of Formula 1-1 can be used to install a Cy^(A)substituent by a number of methods, e.g., by nucleophilic displacementwith an appropriate amine nucleophile with a suitable base (e.g.,triethylamine or DIPEA) in a suitable solvent (e.g., DMF, DMSO,dioxane), or by a suitable cross-coupling reaction, to give compounds ofFormula 1-2. Suitable cross-coupling reactions include but are notlimited to a Buchwald coupling (e.g., in the presence of a palladacycleprecatalyst, such as RuPhod Pd G2), and a Negishi or Suzuki coupling(e.g., in the presence of a palladacycle precatalyst, such as Xphos PdG2). Examples of different cross-coupling procedures include Stille (ACSCatalysis 2015, 5, 3040-3053), Suzuki (Tetrahedron 2002, 58, 9633-9695),Sonogashira (Chem. Soc. Rev. 2011, 40, 5084-5121), Negishi (ACSCatalysis 2016, 6, 1540-1552), Buchwald-Hartwig amination (Chem. Sci.2011, 2, 27-50), and Cu-catalyzed amination (Org. React. 2014, 85,1-688), among others.

Reduction of the nitro group with an appropriate reducing agent (e.g.,iron in the presence of ammonium chloride or hydrogen gas in thepresence of Pd/C catalyst) provides compounds of Formula 1-3. Amide bondformation with acids of Formula 1-5 (e.g., using HATU and a base such asHunig's base) provides compounds of the desired Formula (I) or (F).

The acids of Formula 1-5 can be prepared from the compounds of Formula1-4 using a cross coupling, such as Suzuki (e.g., in the presence of apalladacycle precatalyst, such as Xphos Pd G2) or Stille (e.g., in theprecense of a palladium catalyst such as (PPh₃)₂PdCl₂ and base such astriethylamine).

HPK1 Kinase

Studies have established that HPK1 is a negative regulator of T cell andB cell activation (Hu, M. C., et al., Genes Dev, 1996. 10(18): p.2251-64; Kiefer, F., et al., EMBO J, 1996. 15(24): p. 7013-25).HPK1-deficient mouse T cells showed dramatically increased activation ofTCR proximal signaling, enhanced IL-2 production, andhyper-proliferation in vitro upon anti-CD3 stimulation (Shui, J. W., etal., Nat Immunol, 2007. 8(1): p. 84-91). Similar to T cells, HPK1knockout B cells produced much higher levels of IgM and IgG isoformsafter KLH immunization and displayed hyper-proliferation potentially asa result of enhanced BCR signaling. Wang, X., et al., J Biol Chem, 2012.287(14): p. 11037-48. Mechanistically, during TCR or BCR signaling, HPK1is activated by LCK/ZAP70 (T cells) or SYK/LYN (B cells) mediated-Tyr379phosphorylation and its subsequent binding to adaptor protein SLP-76 (Tcells) or BLNK (B cells) (Wang, X., et al., J Biol Chem, 2012. 287(14):p. 11037-48). Activated HPK1 phosphorylates SLP-76 on Ser376 or BLNK onThr152, leading to the recruitment of signaling molecule 14-3-3 andultimate ubiquitination-mediated degradation of SLP-76 or BLNK (Liou,J., et al., Immunity, 2000. 12(4): p. 399-408; Di Bartolo, V., et al., JExp Med, 2007. 204(3): p. 681-91). As SLP-76 and BLNK are essential forTCR/BCR-mediated signaling activation (e.g. ERK, phospholipase Cγ1,calcium flux, and NFAT activation), HPK1-mediated downregulation ofthese adaptor proteins provide a negative feedback mechanism toattenuate signaling intensity during T cell or B cell activation (Wang,X., et al., J Biol Chem, 2012. 287(14): p. 11037-48).

The bone marrow-derived dendritic cells (BDMCs) from HPK1 knockout miceshowed higher expression of co-stimulatory molecules (e.g. CD80/CD86)and enhanced production of proinflammatory cytokines (IL-12, TNF-α etc),and demonstrated superior ability to stimulate T cell proliferation invitro and in vivo as compared to wild-type DCs (Alzabin, S., et al., JImmunol, 2009. 182(10): p. 6187-94). These data suggest that HPK1 isalso an important negative regulator of dendritic cell activation(Alzabin, S., et al., J Immunol, 2009. 182(10): p. 6187-94). However,the signaling mechanisms underlying HPK-1 mediated negative regulationof DC activation remains to be elucidated.

In contrast, HPK1 appears to be a positive regulator of suppressivefunctions of regulatory T cells (Treg) (Sawasdikosol, S. et al., Thejournal of immunology, 2012. 188(supplement 1): p. 163). HPK1 deficientmouse Foxp3+ Tregs were defective in suppressing TCR-induced effector Tcell proliferation, and paradoxically gained the ability to produce IL-2following TCR engagement (Sawasdikosol, S. et al., The Journal ofImmunology, 2012. 188(supplement 1): p. 163). These data suggest thatHPK1 is an important regulator of Treg functions and peripheralself-tolerance.

HPK1 was also involved in PGE2-mediated inhibition of CD4+ T cellactivation (Ikegami, R., et al., J Immunol, 2001. 166(7): p. 4689-96).Studies published in US 2007/0087988 indicated that HPK1 kinase activitywas increased by exposure to physiological concentrations of PGE2 inCD4+ T cells and this effect was mediated by PEG2-induced PKAactivation. The proliferation of HPK1 deficient T cells was resistant tothe suppressive effects of PGE2 (see US 2007/0087988). Therefore,PGE2-mediated activation of HPK1 may represent a novel regulatorypathway of modulating immune response.

The present disclosure provides methods of modulating (e.g., inhibiting)HPK1 activity, by contacting HPK1 with a compound of the invention, or apharmaceutically acceptable salt thereof. In some embodiments, thecontacting can be administering to a patient a compound provided herein,or a pharmaceutically acceptable salt thereof. In certain embodiments,the compounds of the present disclosure, or pharmaceutically acceptablesalts thereof, are useful for therapeutic administration to enhance,stimulate and/or increase immunity in cancer. For example, a method oftreating a disease or disorder associated with inhibition of HPK1interaction can include administering to a patient in need thereof atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt thereof. The compounds of the presentdisclosure can be used alone, in combination with other agents ortherapies or as an adjuvant or neoadjuvant for the treatment of diseasesor disorders, including cancers. For the uses described herein, any ofthe compounds of the disclosure, including any of the embodimentsthereof, may be used.

Examples of cancers that are treatable using the compounds of thepresent disclosure include, but are not limited to, bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular malignant melanoma, uterine cancer, ovarian cancer, rectalcancer, cancer of the anal region, stomach cancer, testicular cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, endometrial cancer, carcinoma of the cervix, carcinoma ofthe vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin'slymphoma, cancer of the esophagus, cancer of the small intestine, cancerof the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, chronic or acute leukemiasincluding acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors ofchildhood, lymphocytic lymphoma, cancer of the bladder, cancer of thekidney or urethra, carcinoma of the renal pelvis, neoplasm of thecentral nervous system (CNS), primary CNS lymphoma, tumor angiogenesis,spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi'ssarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma,environmentally induced cancers including those induced by asbestos, andcombinations of said cancers.

In some embodiments, cancers treatable with compounds of the presentdisclosure include melanoma (e.g., metastatic malignant melanoma), renalcancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormonerefractory prostate adenocarcinoma), breast cancer, triple-negativebreast cancer, colon cancer and lung cancer (e.g. non-small cell lungcancer and small cell lung cancer). Additionally, the disclosureincludes refractory or recurrent malignancies whose growth may beinhibited using the compounds of the disclosure.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to, solid tumors(e.g., prostate cancer, colon cancer, esophageal cancer, endometrialcancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer,pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancersof the head and neck, thyroid cancer, glioblastoma, sarcoma, bladdercancer, etc.), hematological cancers (e.g., lymphoma, leukemia such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed orrefractory NHL and recurrent follicular), Hodgkin lymphoma or multiplemyeloma) and combinations of said cancers.

In some embodiments, diseases and indications that are treatable usingthe compounds of the present disclosure include, but are not limited tohematological cancers, sarcomas, lung cancers, gastrointestinal cancers,genitourinary tract cancers, liver cancers, bone cancers, nervous systemcancers, gynecological cancers, and skin cancers.

Exemplary hematological cancers include lymphomas and leukemias such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsedor refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasiasyndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiplemyeloma, cutaneous T-cell lymphoma, Waldenstrom's Macroglubulinemia,hairy cell lymphoma, chronic myelogenic lymphoma and Burkitt's lymphoma.

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, andteratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), smallcell lung cancer, bronchogenic carcinoma (squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,chondromatous hamartoma, and mesothelioma.

Exemplary gastrointestinal cancers include cancers of the esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma),large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma), and colorectal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney(adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma).

Exemplary liver cancers include hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors Exemplary nervous system cancers include cancers of the skull(osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma,glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma,congenital tumors), and spinal cord (neurofibroma, meningioma, glioma,sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.

Exemplary gynecological cancers include cancers of the uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),and fallopian tubes (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, squamouscell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, molesdysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. In someembodiments, diseases and indications that are treatable using thecompounds of the present disclosure include, but are not limited to,sickle cell disease (e.g., sickle cell anemia), triple-negative breastcancer (TNBC), myelodysplastic syndromes, testicular cancer, bile ductcancer, esophageal cancer, and urothelial carcinoma.

Exemplary head and neck cancers include glioblastoma, melanoma,rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas,adenocarcinomas, oral cancer, laryngeal cancer, nasopharyngeal cancer,nasal and paranasal cancers, thyroid and parathyroid cancers.

In some embodiments, HPK1 inhibitors may be used to treat tumorsproducing PGE2 (e.g. Cox-2 overexpressing tumors) and/or adenosine (CD73and CD39 over-expressing tumors). Overexpression of Cox-2 has beendetected in a number of tumors, such as colorectal, breast, pancreaticand lung cancers, where it correlates with a poor prognosis.Overexpression of COX-2 has been reported in hematological cancer modelssuch as RAJI (Burkitt's lymphoma) and U937 (acute promonocytic leukemia)as well as in patient's blast cells. CD73 is up-regulated in varioushuman carcinomas including those of colon, lung, pancreas and ovary.Importantly, higher expression levels of CD73 are associated with tumorneovascularization, invasiveness, and metastasis and with shorterpatient survival time in breast cancer.

As used herein, the term “contacting” refers to the bringing together ofthe indicated moieties in an in vitro system or an in vivo system suchthat they are in sufficient physical proximity to interact.

The terms “individual” or “patient,” used interchangeably, refer to anyanimal, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and mostpreferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

In some embodiments, the compounds of the invention are useful inpreventing or reducing the risk of developing any of the diseasesreferred to herein; e.g., preventing or reducing the risk of developinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

Combination Therapies

I. Immune-Checkpoint Therapies

In some embodiments, the HPK1 inhibitors provided herein can be used incombination with one or more immune checkpoint inhibitors for thetreatment of cancer as described herein. Compounds of the presentdisclosure can be used in combination with one or more immune checkpointinhibitors. Exemplary immune checkpoint inhibitors include inhibitorsagainst immune checkpoint molecules such as CD20, CD28, CD39, CD40,CD122, CD96, CD73, CD47, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM,arginase, CD137 (also known as 4-1BB), ICOS, B7-H3, B7-H4, BTLA, CTLA-4,LAG3, TIM3, VISTA, TIGIT, PD-1, PD-L1 and PD-L2. In some embodiments,the immune checkpoint molecule is a stimulatory checkpoint moleculeselected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137. In someembodiments, the immune checkpoint molecule is an inhibitory checkpointmolecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3,PD-1, TIM3, TIGIT, and VISTA. In some embodiments, the compounds of thedisclosure provided herein can be used in combination with one or moreagents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors,CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.

In some embodiments, the compounds provided herein can be used incombination with one or more agonists of immune checkpoint molecules,e.g., OX40, CD27, GITR, and CD137 (also known as 4-1BB).

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), durvalumab (Imfinzi®),pidilizumab, SHR-1210, PDR001, MGA012, PDR001, AB122, or AMP-224. Insome embodiments, the anti-PD-1 monoclonal antibody is nivolumab orpembrolizumab. In some embodiments, the anti-PD1 antibody ispembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody isMGA012. In some embodiments, the anti-PD1 antibody is SHR-1210. Otheranti-cancer agent(s) include antibody therapeutics such as 4-1BB (e.g.urelumab, utomilumab).

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1 and PD-L1, e.g., an anti-PD-1/PD-L1 monoclonalantibody. In some embodiments, the anti-PD-1/PD-L1 is MCLA-136.

In some embodiments, the inhibitor is MCLA-145.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab,AGEN1884, or CP-675,206.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CSF1R, e.g., an anti-CSF1R antibody. In someembodiments, the anti-CSF1R antibody is IMC-CS4 or RG7155.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, IMP321, GSK2831781, orINCAGN2385.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228,BMS-986156, GWN323, or MEDI1873.

In some embodiments, the inhibitor of an immune checkpoint molecule isan agonist of OX40, e.g., OX40 agonist antibody or OX40L fusion protein.In some embodiments, the anti-OX40 antibody is INCAGN01949, MEDI0562,MEDI6469, MOXR-0916, PF-04518600, GSK3174998, or BMS-986178. In someembodiments, the OX40L fusion protein is MEDI6383.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFβ receptor.

In some embodiments, the compounds of the disclosure can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDO 1,TDO, or arginase. Examples of IDO 1 inhibitors include epacadostat,NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196. Anexample of an arginase inhibitor is CB-1158.

As provided throughout, the additional compounds, inhibitors, agents,etc. can be combined with the present compound in a single or continuousdosage form, or they can be administered simultaneously or sequentiallyas separate dosage forms.

II. Cancer Therapies

Cancer cell growth and survival can be impacted by multiple signalingpathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Examples of agents that may be combined with compounds ofthe present disclosure include inhibitors of the PI3K-AKT-mTOR pathway,inhibitors of the Raf-MAPK pathway, inhibitors of JAK-STAT pathway,inhibitors of beta catenin pathway, inhibitors of notch pathway,inhibitors of hedgehog pathway, inhibitors of Pim kinases, andinhibitors of protein chaperones and cell cycle progression. Targetingmore than one signaling pathway (or more than one biological moleculeinvolved in a given signaling pathway) may reduce the likelihood ofdrug-resistance arising in a cell population, and/or reduce the toxicityof treatment.

The compounds of the present disclosure can be used in combination withone or more other enzyme/protein/receptor inhibitors for the treatmentof diseases, such as cancer. Examples of cancers include solid tumorsand liquid tumors, such as blood cancers. For example, the compounds ofthe present disclosure can be combined with one or more inhibitors ofthe following kinases for the treatment of cancer: Akt1, Akt2, Akt3,TGF-3R, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK,MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR,CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4,c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2,EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK,ABL, ALK and B-Raf. In some embodiments, the compounds of the presentdisclosure can be combined with one or more of the following inhibitorsfor the treatment of cancer. Non-limiting examples of inhibitors thatcan be combined with the compounds of the present disclosure fortreatment of cancers include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 orFGFR4, e.g., AZD4547, BAY1187982, ARQ087, BGJ398, BIBF1120, TKI258,lucitanib, dovitinib, TAS-120, JNJ-42756493, Debio1347, INCB54828,INCB62079 and INCB63904), a JAK inhibitor (JAK1 and/or JAK2, e.g.,ruxolitinib, baricitinib or INCB39110), an IDO inhibitor (e.g.,epacadostat and NLG919), an LSD1 inhibitor (e.g., GSK2979552, INCB59872and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor (e.g., INCB50797and INCB50465), a PI3K-gamma inhibitor such as a PI3K-gamma selectiveinhibitor, a CSFIR inhibitor (e.g., PLX3397 and LY3022855), a TAMreceptor tyrosine kinases (Tyro-3, Axl, and Mer), an angiogenesisinhibitor, an interleukin receptor inhibitor, bromo and extra terminalfamily members inhibitors (for example, bromodomain inhibitors or BETinhibitors such as OTX015, CPI-0610, INCB54329 and INCB57643) and anadenosine receptor antagonist or combinations thereof. Inhibitors of HDAC such as panobinostat and vorinostat. Inhibitors of c-Met such asonartumzumab, tivantnib, and INC-280. Inhibitors of BTK such asibrutinib. Inhibitors of mTOR such as rapamycin, sirolimus,temsirolimus, and everolimus. Inhibitors of Raf, such as vemurafenib anddabrafenib. Inhibitors of MEK such as trametinib, selumetinib andGDC-0973. Inhibitors of Hsp90 (e.g., tanespimycin), cyclin dependentkinases (e.g., palbociclib), PARP (e.g., olaparib) and Pim kinases(LGH447, INCB053914 and SGI-1776) can also be combined with compounds ofthe present disclosure.

Compounds of the present disclosure can be used in combination with oneor more agents for the treatment of diseases such as cancer. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include bendamustine, nitrogen mustards, ethylenimine derivatives,alkyl sulfonates, nitrosoureas and triazenes, uracil mustard,chlormethine, cyclophosphamide (Cytoxan™), ifosfamide, melphalan,chlorambucil, pipobroman, triethylene-melamine,triethylenethiophosphoramine, busulfan, carmustine, lomustine,streptozocin, dacarbazine, and temozolomide. In some embodiments, theproteasome inhibitor is carfdzomib. In some embodiments, thecorticosteroid is dexamethasone (DEX). In some embodiments, theimmunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).

The compounds of the present disclosure can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation therapy, tumor-targeted therapy, adjuvanttherapy, immunotherapy or surgery. Examples of immunotherapy includecytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207immunotherapy, cancer vaccine, monoclonal antibody, adoptive T celltransfer, CAR (Chimeric antigen receptor) T cell treatment as a boosterfor T cell activation, oncolytic virotherapy and immunomodulating smallmolecules, including thalidomide or JAK1/2 inhibitor and the like. Thecompounds can be administered in combination with one or moreanti-cancer drugs, such as a chemotherapeutics. Examplechemotherapeutics include any of: abarelix, abiraterone, afatinib,aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol,altretamine, amsacrine, anastrozole, aphidicolon, arsenic trioxide,asparaginase, axitinib, azacitidine, bevacizumab, bexarotene,baricitinib, bicalutamide, bleomycin, bortezombi, bortezomib, brivanib,buparlisib, busulfan intravenous, busulfan oral, calusterone, camptosar,capecitabine, carboplatin, carmustine, cediranib, cetuximab,chlorambucil, cisplatin, cladribine, clofarabine, crizotinib,cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin,dalteparin sodium, dasatinib, dactinomycin, daunorubicin, decitabine,degarelix, denileukin, denileukin diftitox, deoxycoformycin,dexrazoxane, docetaxel, doxorubicin, droloxafine, dromostanolonepropionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin,epothilones, erlotinib, estramustine, etoposide phosphate, etoposide,exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine,fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumabozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan,idarubicin, idelalisib, ifosfamide, imatinib mesylate, interferon alfa2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole,leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine,megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen,mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolonephenpropionate, navelbene, necitumumab, nelarabine, neratinib,nilotinib, nilutamide, nofetumomab, oserelin, oxaliplatin, paclitaxel,pamidronate, panitumumab, pazopanib, pegaspargase, pegfdgrastim,pemetrexed disodium, pentostatin, pilaralisib, pipobroman, plicamycin,ponatinib, porfimer, prednisone, procarbazine, quinacrine, ranibizumab,rasburicase, regorafenib, reloxafine, revlimid, rituximab, ruxolitinib,sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen,tegafur, temozolomide, teniposide, testolactone, thalidomide,thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab,tretinoin, triptorelin, uracil mustard, valrubicin, vandetanib,vinblastine, vincristine, vindesine, vinorelbine, vorinostat andzoledronate.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4 (e.g., ipilimumab or tremelimumab), 4-1BB, antibodies to PD-1 andPD-L1, or antibodies to cytokines (IL-10, TGF-β, etc.). Examples ofantibodies to PD-1 and/or PD-L1 that can be combined with compounds ofthe present disclosure for the treatment of cancer or infections such asviral, bacteria, fungus and parasite infections include, but are notlimited to, nivolumab, pembrolizumab, MPDL3280A, MEDI-4736 and SHR-1210.

Other anti-cancer agents include inhibitors of kinases associated cellproliferative disorder. These kinases include but not limited toAurora-A, CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, ephrin receptorkinases, CHK1, CHK2, SRC, Yes, Fyn, Lck, Fer, Fes, Syk, Itk, Bmx, GSK3,JNK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC, Rsk and SGK.

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

The compounds of the present disclosure can further be used incombination with one or more anti-inflammatory agents, steroids,immunosuppressants or therapeutic antibodies. The steroids include butare not limited to 17 alpha-ethinylestradiol, diethylstilbestrol,testosterone, prednisone, fluoxymesterone, methylprednisolone,methyltestosterone, prednisolone, triamcinolone, chlorotrianisene,hydroxyprogesterone, aminoglutethimide, and medroxyprogesteroneacetate.

The compounds of the present disclosure can also be used in combinationwith lonafarnib (SCH6636), tipifarnib (R115777), L778123, BMS 214662,tezacitabine (MDL 101731), Sml1, triapine, didox, trimidox and amidox.

The compounds of Formula (I), (F), or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,or salts thereof can be combined with another immunogenic agent, such ascancerous cells, purified tumor antigens (including recombinantproteins, peptides, and carbohydrate molecules), cells, and cellstransfected with genes encoding immune stimulating cytokines.Non-limiting examples of tumor vaccines that can be used includepeptides of melanoma antigens, such as peptides of gp100, MAGE antigens,Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to expressthe cytokine GM-CSF.

The compounds of Formula (I), (F) or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,or salts thereof can be used in combination with a vaccination protocolfor the treatment of cancer. In some embodiments, the tumor cells aretransduced to express GM-CSF. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compoundsof the present disclosure can be used in combination with tumor specificantigen such as heat shock proteins isolated from tumor tissue itself.In some embodiments, the compounds of Formula (I), (F), or any of theformulas as described herein, a compound as recited in any of the claimsand described herein, or salts thereof can be combined with dendriticcells immunization to activate potent anti-tumor responses.

The compounds of the present disclosure can be used in combination withbispecific macrocyclic peptides that target Fe alpha or Fe gammareceptor-expressing effectors cells to tumor cells. The compounds of thepresent disclosure can also be combined with macrocyclic peptides thatactivate host immune responsiveness.

The compounds of the present disclosure can be used in combination withbone marrow transplant for the treatment of a variety of tumors ofhematopoietic origin.

Suitable antiviral agents contemplated for use in combination with thecompounds of the present disclosure can comprise nucleoside andnucleotide reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs), protease inhibitors and otherantiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddl);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil[bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′,3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6-diamino-purine dioxolane); and lodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione);and (+)-calanolide A (NSC-675451) and B. Typical suitable proteaseinhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538);indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir(BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Otherantiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No. 11607.

When more than one pharmaceutical agent is administered to a patient,they can be administered simultaneously, separately, sequentially, or incombination (e.g., for more than two agents).

In some embodiments, the compounds of the disclosure can be used incombination with INCB086550.

Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the presentdisclosure can be administered in the form of pharmaceuticalcompositions. Thus the present disclosure provides a compositioncomprising a compound of Formula (I), (F), or any of the formulas asdescribed herein, a compound as recited in any of the claims anddescribed herein, or a pharmaceutically acceptable salt thereof, or anyof the embodiments thereof, and at least one pharmaceutically acceptablecarrier or excipient. These compositions can be prepared in a mannerwell known in the pharmaceutical art, and can be administered by avariety of routes, depending upon whether local or systemic treatment isindicated and upon the area to be treated. Administration may be topical(including transdermal, epidermal, ophthalmic and to mucous membranesincluding intranasal, vaginal and rectal delivery), pulmonary (e.g., byinhalation or insufflation of powders or aerosols, including bynebulizer; intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be,e.g., by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the present disclosure or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers or excipients. In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, e.g., a capsule, sachet, paper, orother container. When the excipient serves as a diluent, it can be asolid, semi-solid, or liquid material, which acts as a vehicle, carrieror medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, e.g., up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art see, e.g., WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicifiedmicrocrystalline cellulose (SMCC) and at least one compound describedherein, or a pharmaceutically acceptable salt thereof. In someembodiments, the silicified microcrystalline cellulose comprises about98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release compositioncomprising at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and at least one component selected from microcrystallinecellulose, lactose monohydrate, hydroxypropyl methylcellulose andpolyethylene oxide. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and microcrystalline cellulose, lactose monohydrate andhydroxypropyl methylcellulose. In some embodiments, the compositioncomprises at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and microcrystalline cellulose, lactosemonohydrate and polyethylene oxide. In some embodiments, the compositionfurther comprises magnesium stearate or silicon dioxide. In someembodiments, the microcrystalline cellulose is Avicel PH102™. In someembodiments, the lactose monohydrate is Fast-flo 316™. In someembodiments, the hydroxypropyl methylcellulose is hydroxypropylmethylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and/orhydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV™). Insome embodiments, the polyethylene oxide is polyethylene oxide WSR 1105(e.g., Poly ox WSR 1105™).

In some embodiments, a wet granulation process is used to produce thecomposition. In some embodiments, a dry granulation process is used toproduce the composition.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. In some embodiments, eachdosage contains about 10 mg of the active ingredient. In someembodiments, each dosage contains about 50 mg of the active ingredient.In some embodiments, each dosage contains about 25 mg of the activeingredient. The term “unit dosage forms” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient.

The components used to formulate the pharmaceutical compositions are ofhigh purity and are substantially free of potentially harmfulcontaminants (e.g., at least National Food grade, generally at leastanalytical grade, and more typically at least pharmaceutical grade).Particularly for human consumption, the composition is preferablymanufactured or formulated under Good Manufacturing Practice standardsas defined in the applicable regulations of the U.S. Food and DrugAdministration. For example, suitable formulations may be sterile and/orsubstantially isotonic and/or in full compliance with all GoodManufacturing Practice regulations of the U.S. Food and DrugAdministration.

The active compound may be effective over a wide dosage range and isgenerally administered in a therapeutically effective amount. It will beunderstood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms and the like.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, e.g., about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, e.g., liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, e.g., glycerol,hydroxy ethyl cellulose, and the like. In some embodiments, topicalformulations contain at least about 0.1, at least about 0.25, at leastabout 0.5, at least about 1, at least about 2 or at least about 5 wt %of the compound of the invention. The topical formulations can besuitably packaged in tubes of, e.g., 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers or stabilizers will resultin the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds ofthe disclosure (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating HPK1 protein in tissuesamples, including human, and for identifying HPK1 ligands by inhibitionbinding of a labeled compound. Substitution of one or more of the atomsof the compounds of the present disclosure can also be useful ingenerating differentiated ADME (Adsorption, Distribution, Metabolism andExcretion). Accordingly, the present invention includes HPK1 bindingassays that contain such labeled or substituted compounds.

The present disclosure further includes isotopically-labeled compoundsof the disclosure. An “isotopically” or “radio-labeled” compound is acompound of the disclosure where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present disclosure include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. For example, one or more hydrogenatoms in a compound of the present disclosure can be replaced bydeuterium atoms (e.g., one or more hydrogen atoms of a C₁₋₆ alkyl groupof Formula (I) or (F) can be optionally substituted with deuteriumatoms, such as —CD₃ being substituted for —CH₃). In some embodiments,alkyl groups in Formula (I) or (F) can be perdeuterated.

One or more constituent atoms of the compounds presented herein can bereplaced or substituted with isotopes of the atoms in natural ornon-natural abundance. In some embodiments, the compound includes atleast one deuterium atom. In some embodiments, the compound includes twoor more deuterium atoms. In some embodiments, the compound includes 1-2,1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all of thehydrogen atoms in a compound can be replaced or substituted by deuteriumatoms.

Synthetic methods for including isotopes into organic compounds areknown in the art (Deuterium Labeling in Organic Chemistry by Alan F.Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissanceof H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and JochenZimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistryof Isotopic Labelling by James R. Hanson, Royal Society of Chemistry,2011). Isotopically labeled compounds can be used in various studiessuch as NMR spectroscopy, metabolism experiments, and/or assays.

Substitution with heavier isotopes, such as deuterium, may affordcertain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances, (seee.g., A. Kerekes et. al. J. Med Chem. 2011, 54, 201-210; R. Xu et. al.J. Label Compd Radiopharm. 2015, 58, 308-312). In particular,substitution at one or more metabolism sites may afford one or more ofthe therapeutic advantages.

The radionuclide that is incorporated in the instant radio-labeledcompounds will depend on the specific application of that radio-labeledcompound. For example, for in vitro adenosine receptor labeling andcompetition assays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹Ior ³⁵S can be useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I,¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br can be useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments, the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

The present disclosure can further include synthetic methods forincorporating radio-isotopes into compounds of the disclosure. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of disclosure.

A labeled compound of the invention can be used in a screening assay toidentify and/or evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind a HPK1 protein by monitoring itsconcentration variation when contacting with the HPK1, through trackingof the labeling. For example, a test compound (labeled) can be evaluatedfor its ability to reduce binding of another compound which is known tobind to a HPK1 protein (i.e., standard compound). Accordingly, theability of a test compound to compete with the standard compound forbinding to the HPK1 protein directly correlates to its binding affinity.Conversely, in some other screening assays, the standard compound islabeled and test compounds are unlabeled. Accordingly, the concentrationof the labeled standard compound is monitored in order to evaluate thecompetition between the standard compound and the test compound, and therelative binding affinity of the test compound is thus ascertained.

Kits

The present disclosure also includes pharmaceutical kits useful, e.g.,in the treatment or prevention of diseases or disorders associated withthe activity of HPK1, such as cancer or infections, which include one ormore containers containing a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula (I), (F), orany of the embodiments thereof. Such kits can further include one ormore of various conventional pharmaceutical kit components, such as,e.g., containers with one or more pharmaceutically acceptable carriers,additional containers, etc., as will be readily apparent to thoseskilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to inhibitthe activity of HPK1 according to at least one assay described herein.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Preparatory LC-MS purifications of some of the compounds preparedwere performed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity check.

The compounds separated were typically subjected to analytical liquidchromatography mass spectrometry (LCMS) for purity check under thefollowing conditions: Instrument; Agilent 1100 series, LC/MSD, Column:Waters Sunfire™ C₁₈ 5 μm particle size, 2.1×5.0 mm, Buffers: mobilephase A: 0.025% TFA in water and mobile phase B: acetonitrile; gradient2% to 80% of B in 3 minutes with flow rate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) inwater and mobile phase B: acetonitrile; the flow rate was 30 mL/minute,the separating gradient was optimized for each compound using theCompound Specific Method Optimization protocol as described in theliterature [see “Preparative LCMS Purification: Improved CompoundSpecific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs,J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate used withthe 30×100 mm column was 60 mL/minute.

pH=10 purifications: Waters XBridge C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.15% NH₄OH in water and mobilephase B: acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature [See“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)]. Typically, the flow rate used with 30×100 mm columnwas 60 mL/minute.”

The following abbreviations may be used herein: AcOH (acetic acid); Ac₂O(acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc(t-butoxycarbonyl); BOP((benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate); br (broad); Cbz (carboxybenzyl); calc,(calculated); d (doublet); dd (doublet of doublets); DBU(1,8-diazabicyclo[5.4.0]undec-7-ene); DCM (dichloromethane); DIAL)(N,N′-diisopropyl azidodicarboxylate); DIEA (N,N-diisopropylethylamine);DIPEA (N,N-diisopropylethylamine); DIBAL (diisobutylaluminium hydride);DMF (N,N-dimethylformamide); Et (ethyl); EtOAc (ethyl acetate); FCC(flash column chromatography); g (gram(s)); h (hour(s)); HATU(N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate); HCl (hydrochloric acid); HPLC (high performanceliquid chromatography); Hz (hertz); J (coupling constant); LCMS (liquidchromatography—mass spectrometry); LDA (lithium diisopropylamide); m(multiplet); M (molar); wCPBA (3-chloroperoxybenzoic acid); MS (Massspectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg(milligram(s)); min. (minutes(s)); mL (milliliter(s)); mmol(millimole(s)); N (normal); nM (nanomolar); NMP (N-methylpyrrolidinone);NMR (nuclear magnetic resonance spectroscopy); OTf(trifluoromethanesulfonate); Ph (phenyl); pM (picomolar); RP-HPLC(reverse phase high performance liquid chromatography); r.t. (roomtemperature), s (singlet); t (triplet or tertiary); TBS(tert-butyldimethylsilyl); tert (tertiary); tt (triplet of triplets);TFA (trifluoroacetic acid); THF (tetrahydrofuran); μg (microgram(s)); μL(microliter(s)); μM (micromolar); wt % (weight percent). Brine issaturated aqueous sodium chloride. In vacuo is under vacuum.

Example 1.N-(2-((1R,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. 2-(2-Fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic Acid

A mixture of 2-chloropyrimidine-4-carboxylic acid (9.0 g, 56.8 mmol),(2-fluoro-6-methoxyphenyl)boronic acid (11.58 g, 68.1 mmol), XPhosPd G2(1.340 g, 1.703 mmol) and potassium phosphate, tribasic (24.10 g, 114mmol) were combined with 1,4-dioxane (100 mL) and water (20.00 mL). Thereaction flask was evacuated, back filled with nitrogen, and then heatedto 80° C. for 2 h. The reaction mixture was then cooled to roomtemperature, treated with water and diluted with ethyl acetate. Theaqueous phase was separated and acidified with 1 N HCl. The resultingsolid was collected by filtration and washed with water. After airdrying, it was used in Step 4 without further purification. LCMScalculated for C₁₂H₁₀FN₂O₃ (M+H)⁺: m/z=249.2; found 249.2.

Step 2. (1R,4R)-tert-Butyl5-(4-fluoro-2-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

A solution of 1,4-difluoro-2-nitrobenzene (257 mg, 1.6 mmol) andtert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (320 mg,1.6 mmol) in DMSO (2.5 mL) was treated with triethylamine (338 μl, 2.4mmol). The reaction mixture was heated to 80° C. for 3 h. After coolingto room temperature, the reaction mixture was diluted withdichloromethane and washed with brine. The separated organic phase wasdried over sodium sulfate and concentrated. The crude product was usedin the next step without further purification. LCMS calculated forC₁₂H₁₃FN₃O₄ (M+H—C₄H₈)⁺: m/z=282.1; found 282.1.

Step 3. (1R,4R)-tert-Butyl5-(2-amino-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

A mixture of tert-butyl(1R,4R)-5-(4-fluoro-2-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(545 mg, 1.6 mmol), iron (451 mg, 8.1 mmol) and ammonium chloride (518mg, 9.7 mmol) in THF (2 mL), water (2 mL) and methanol (2 mL) wasstirred at 60° C. for 3 h. After cooling to room temperature, thereaction mixture was filtered through a plug of Celite and diluted withdichloromethane. The organic phase was separated, washed with brine,dried over sodium sulfate and the solvents were evaporated in vacuo. Thecrude product was used in the next step without further purification.LCMS calculated for C₁₆H₂₃FN₃O₂ (M+H)⁺: m/z=308.2; Found: 308.2.

Step 4.N-(2-((1R,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

HATU (178 mg, 0.468 mmol) was added to a solution of tert-butyl(1R,4R)-5-(2-amino-4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(96 mg, 0.312 mmol), 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylicacid (from Step 1; 78 mg, 0.312 mmol) and DIPEA (109 μl, 0.625 mmol) inDMF (2 mL). The reaction mixture was stirred at room temperature for 30min, and then treated with water. The precipitated product was collectedby filtration, washed with water and air dried. The solid residue wasthen re-dissolved in TFA and the solution was stirred at roomtemperature for 10 min. The mixture was then diluted with acetonitrileand purified with prep-LCMS (XBridge C18 column, eluting with a gradientof acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toisolate the title compound as the TFA salt. LCMS calculated forC₂₃H₂₂F₂N₅O₂ (M+H)⁺: m/z=438.2; Found: 438.2.

Example 2.(S)—N-(2-(3-Aminopyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 1, using (S)-pyrrolidin-3-amine insteadof tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate asstarting material. LCMS calculated for C₂₂H₂₂F₂N₅O₂ (M+H)⁺: m/z=426.2;Found: 426.3.

Example 3.(R)—N-(2-(2-(Aminomethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 1, using (R)-tert-butylpyrrolidin-2-ylmethylcarbamate instead of tert-butyl(1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as startingmaterial. LCMS calculated for C₂₃H₂₄F₂N₅O₂ (M+H)⁺: m/z=440.2; Found:440.1.

Example 4.(R)—N-(5-Fluoro-2-(2-(hydroxymethyl)pyrrolidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 1, using (R)-pyrrolidin-2-yl methanolinstead of tert-butyl(1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as startingmaterial. LCMS calculated for C₂₃H₂₃F₂N₄O₃ (M+H)⁺: m/z=441.2; Found:441.1.

Example 5.(R)—N-(5-Fluoro-2-(2-(methoxymethyl)pyrrolidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 1, using(R)-2-(methoxymethyl)pyrrolidine instead of tert-butyl(1R,4R)-2f-diazabicyclo[2.2.1]heptane-2-carboxylate as startingmaterial. LCMS calculated for C₂₄H₂₅F₂N₄O₃ (M+H)⁺: m/z=455.2; Found:455.3.

Example 6.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The free base and TFA salt of the title compound was prepared accordingto the procedures described in Example 1, (and detailed below) usingtert-butyl (3S,5S)-5-(hydroxymethyl)-pyrrolidin-3-ylcarbamate instead oftert-butyl (1R4R)-2f-diazabicyclo[2.2.1]heptane-2-carboxylate asstarting material.

Step 1. tert-Butyl((3S,5S)-1-(4-fluoro-2-nitrophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate

A solution of 1,4-difluoro-2-nitrobenzene (68.2 μL, 0.629 mmol) andtert-butyl ((3S,5S) 5-(hydroxymethyl)pyrrolidin-3-yl)carbamate (136 mg,0.629 mmol) in DMSO (2.5 mL) was treated with triethylamine (131 μL,0.943 mmol) and the reaction mixture was heated to 80° C. for 3 hrs.After cooling to r.t., the reaction mixture was diluted with DCM, washedwith brine, dried over sodium sulfate and the solvent was evaporatedunder vacuum. The obtained crude product was used in the next stepwithout further purification. LCMS calculated for C₁₂H₁₅FN₃O₅(M+H—C₄H₈)⁺: m/z=300.1; found 300.1.

Step 2. tert-Butyl((3S,5S)-1-(2-amino-4-fluorophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate

A mixture of tert-butyl((3S,5S)-1-(4-fluoro-2-nitrophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(100 mg, 0.281 mmol), iron (79 mg, 1.407 mmol) and ammonium chloride (90mg, 1.7 mmol) in THF (2 mL), water (2 mL) and methanol (2 mL) wasstirred at 60° C. for 3 hrs. After cooling to r.t., the mixture wasfiltered through a plug of Celite and diluted with DCM. The organicphase was separated, washed with brine, dried over sodium sulfate andthe solvents were evaporated under vacuum. The obtained crude productwas used in the next step without further purification. LCMS calculatedfor C₁₆H₂₅FN₃O₃(M+H)⁺: m/z=326.2; Found: 326.2.

Step 3.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

HATU (175 mg, 0.461 mmol) was added to a solution of tert-butyl((3S,5S)-1-(2-amino-4-fluorophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(100 mg, 0.307 mmol),2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid (the product ofExample 1, step 1, 76 mg, 0.307 mmol) and DIPEA (107 μL, 0.615 mmol) inDMF (2 mL). The reaction mixture was stirred at r.t. for 30 mins, thenwater was added and the precipitated product was collected byfiltration, washed with water and air dried. The solid was dissolved inTFA and the resulting solution was stirred at r.t. for 10 mins. Thesolution was then diluted with acetonitrile and purified with prep-LCMS.LCMS calculated for C₂₃H₂₄F₂N₅O₃ (M+H)⁺: m/z=456.2; Found: 456.3.Prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% NH₄OH, at flow rate of 60 mL/min).Free base: 1H NMR (600 MHz, DMSO-d6) δ 9.34-9.18 (m, 1H), 8.25-8.19 (m,1H), 8.18-8.14 (m, 1H), 7.60-7.49 (q, J=7.7 Hz, 1H), 7.49-7.43 (m, 1H),7.08-7.02 (d, J=8.4 Hz, 1H), 7.02-6.94 (m, 2H), 3.78-3.71 (s, 3H),3.38-3.30 (t, J=6.4 Hz, 1H), 3.30-3.23 (m, 1H), 3.23-3.17 (m, 1H),3.17-3.10 (dd, J=11.1, 6.1 Hz, 1H), 2.95-2.88 (t, J=7.4 Hz, 1H),2.88-2.80 (m, 1H), 2.35-2.25 (dt, J=14.1, 8.0 Hz, 1H), 1.25-1.12 (m, 1H)ppm. Prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) TFAsalt: 1H NMR (600 MHz, DMSO-d6) δ 10.78-10.58 (s, 1H), 9.32-9.20 (d,J=5.0 Hz, 1H), 8.24-8.08 (m, 2H), 7.93-7.77 (br, J=5.7 Hz, 2H),7.62-7.53 (td, J=8.4, 6.8 Hz, 1H), 7.53-7.46 (dd, J=8.8, 5.7 Hz, 1H),7.10-7.02 (m, 2H), 7.02-6.93 (t, J=8.8 Hz, 1H), 3.82-3.73 (s, 3H),3.75-3.67 (m, 1H), 3.59-3.51 (m, 1H), 3.30-3.15 (m, 4H), 2.44-2.35 (ddd,J=13.6, 9.1, 7.2 Hz, 1H), 1.81-1.71 (dt, J=13.5, 4.3 Hz, 1H) ppm.

Example 7.N-(5-Fluoro-2-((2S,4S)-4-hydroxy-2-methylpyrrolidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 1, using (3S,5S)-5-methylpyrrolidin-3-ol instead of tert-butyl(1R4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as startingmaterial. LCMS calculated for C₂₃H₂₃F₂N₄O₃ (M+H)⁺: m/z=441.2; Found:441.3.

Example 8.N-(5-Fluoro-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 1, using 2-(pyrrolidin-2-yl)pyridineinstead of tert-butyl(1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as startingmaterial. LCMS calculated for C₂₇H₂₄F₂N₅O₂ (M+H)⁺: m/z=488.2; Found:488.1.

Example 9.N-(5-Fluoro-2-(hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 1, using tert-butylhexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate instead of tert-butyl(1R,4R)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate as startingmaterial. LCMS calculated for C₂₄H₂₄F₂N₅O₂(M+H)⁺: m/z=452.2; Found:452.2.

Example 10.(R)—N-(5-Fluoro-2-(2-methylpiperazin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 1, using (R)-tert-butyl3-methylpiperazine-1-carboxylate instead of tert-butyl(1R,4R)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate as startingmaterial. LCMS calculated for C₂₃H₂₄F₂N₅O₂ (M+H)⁺: m/z=440.2; Found:440.2.

Example 11.(R)—N-(5-Fluoro-2-(2-(hydroxymethyl)piperazin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 1, using (R)-tert-butyl3-(hydroxymethyl)piperazine-1-carboxylate instead of tert-butyl(1R,4R)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate as startingmaterial. LCMS calculated for C₂₃H₂₄F₂N₅O₃ (M+H)⁺: m/z=456.2; Found:456.2.

Example 12.N-(5-Fluoro-2-(3-(hydroxymethyl)morpholino)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 1, using morpholin-3-ylmethanol insteadof tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate asstarting material. LCMS calculated for C₂₃H₂₃F₂N₄O₄ (M+H)⁺: m/z=457.2;Found: 457.2.

Example 13.N-(2-((1R,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-3-bromo-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 1, using1-bromo-2,5-difluoro-3-nitrobenzene instead of1,4-difluoro-2-nitrobenzene as starting material. LCMS calculated forC₂₃H₂₁BrF₂N₅O₂ (M+H)⁺: m/z=516.1; Found: 516.1.

Example 14.N-(2-((1R,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-3-cyanophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 1, using 2-fluoro-3-nitrobenzonitrileinstead of 1,4-difluoro-2-nitrobenzene as starting material. LCMScalculated for C₂₄H₂₂FN₆O₂ (M+H)⁺: m/z=445.2; Found: 445.2.

Example 15.N-(2-((1R,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-3-(pyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A mixture of tert-butyl(1R,4R)-5-(2-bromo-4-fluoro-6-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(from Example 13; 10 mg, 0.016 mmol), pyridin-3-ylboronic acid (4 mg,0.032 mmol), XPhosPd G2 (1.3 mg, 1.6 μmol) and potassium phosphate,tribasic (6.7 mg, 0.032 mmol) was combined with 1,4-dioxane (1 mL) andwater (0.1 mL). The reaction flask was evacuated, back filled withnitrogen, and the mixture was stirred at 80° C. for 1 h. The reactionmixture was cooled to room temperature and the solvents were evaporatedin vacuo. The residue was combined with TFA (1 mL) and stirred at roomtemperature for 10 min. The reaction mixture was diluted with CH₃CN andwater and purified with prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min) to provide the TFA salt of the title compound. LCMS calculatedfor C₂₈H₂₅F₂N₆O₂ (M+H)⁺: m/z=515.2; Found: 515.3.

Example 16.N-(2-((1R,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 15, using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleinstead of pyridin-3-ylboronic acid as starting material. LCMScalculated for C₂₇H₂₆F₂N₇O₂ (M+H)⁺: m/z=518.2; Found: 518.3.

Example 17.N-(2-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-4-(hydroxymethyl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 1, using(2,5-difluoro-4-nitrophenyl)methanol instead of1,4-difluoro-2-nitrobenzene and tert-butyl(1S,4S)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate instead oftert-butyl (1R,4R)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate asstarting material. LCMS calculated for C₂₄H₂₄F₂N₅O₃ (M+H)⁺: m/z=468.2;Found: 468.2. ¹H NMR (600 MHz, DMSO-d₆) δ 10.81-10.70 (s, 1H), 9.33-9.25(d, J=5.0 Hz, 1H), 8.19-8.12 (d, J=5.0 Hz, 1H), 8.12-8.04 (d, 7=11.4 Hz,1H), 7.63-7.52 (q, J=7.9 Hz, 1H), 7.38-7.28 (d, J=7.2 Hz, 1H), 7.13-7.06(d, J=8.5 Hz, 1H), 7.05-6.95 (t, J=8.8 Hz, 1H), 5.28-5.16 (s, 1H),4.57-4.42 (s, 2H), 3.82-3.71 (s, 3H), 3.70-3.60 (s, 1H), 3.54-3.46 (s,1H), 3.26-3.17 (d, J=9.0 Hz, 1H), 3.12-3.04 (d, J=9.0 Hz, 1H), 2.92-2.86(d, J=10.0 Hz, 1H), 2.67-2.59 (d, J=9.7 Hz, 1H), 1.65-1.59 (d, J=9.3 Hz,1H), 1.54-1.38 (d, J=9.1 Hz, 1H) ppm.

Example 18.N-(2-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-4-bromo-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 1, using1-bromo-2,5-difluoro-4-nitrobenzene instead of1,4-difluoro-2-nitrobenzene and tert-butyl(1S,4S)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate instead oftert-butyl (1R,4R)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate asstarting material. LCMS calculated for C₂₃H₂₁BrF₂N₅O₂ (M+H)⁺: m/z=516.1;Found: 516.1.

Example 19.N-(2-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A mixture of tert-butyl(1S,4S)-5-(5-bromo-4-fluoro-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(from Example 18; 10 mg, 0.016 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(6.8 mg, 0.032 mmol), XPhosPd G2 (1.3 mg, 1.6 μmol) and potassiumphosphate, tribasic (6.7 mg, 0.032 mmol) was combined with 1,4-dioxane(1 mL) and water (0.1 mL). The reaction flask was evacuated, back filledwith nitrogen, then stirred at 80° C. for 1 h. The reaction mixture wascooled to room temperature, the solvents were evaporated in vacuo, andTFA (1 mL) was added. The reaction mixture was stirred at roomtemperature for 10 min, then diluted with CH₃CN and water and purifiedwith prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toprovide the TFA salt of the title compound. LCMS calculated forC₂₇H₂₆F₂N₇O₂ (M+H)⁺: m/z=518.2; Found: 518.3. ¹H NMR (600 MHz, DMSO-dis)δ 10.58 (s, 1H), 9.30 (d, J=4.9 Hz, 1H), 8.94 (br, 2H), 8.20-8.15 (m,2H), 8.14 (s, 1H), 7.94 (s, 1H), 7.67-7.53 (m, 2H), 7.09 (d, J=8.5 Hz,1H), 7.02 (t, J=8.7 Hz, 1H), 4.41 (s, 1H), 4.04 (s, 1H), 3.91 (s, 3H),3.78 (s, 3H), 3.51 (d, J=11.0 Hz, 1H), 3.42 (d, J=11.2 Hz, 1H),3.34-3.20 (m, 1H), 3.03 (s, 1H), 1.91 (d, J=10.6 Hz, 1H), 1.77 (d,J=10.7 Hz, 1H) ppm.

Example 20.N-(2-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-4-(6-(hydroxymethyl)pyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 19, using(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methanolinstead of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole asstarting material. LCMS calculated for C₂₉H₂₇F₂N₆O₃ (M+H)⁺: m/z=545.2;Found: 545.3.

Example 21.N-(2-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-4-(6-(methylcarbamoyl)pyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 19, usingN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamideinstead of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole asstarting material. LCMS calculated for C₃₀H₂₈F₂N₇O₃ (M+H)⁺: m/z=572.2;Found: 572.3.

Example 22.N-(2-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 19, using1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-oneinstead of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole asstarting material. LCMS calculated for C₂₉H₂₇F₂N₆O₃ (M+H)⁺: m/z=545.2;Found: 545.3. Example 23.N-(2-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-4-(2-methylpyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 19, using 2-methylpyridin-3-ylboronicacid instead of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole asstarting material. LCMS calculated for C₂₉H₂₇F₂N₆O₂ (M+H)⁺: m/z=529.2;Found: 529.3.

Example 24.N-(2-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-4-(2-methylpyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. (1S,4S)-tert-Butyl5-(5-bromo-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

This compound was prepared according to the procedures described inExample 18, using 4-bromo-2-fluoro-1-nitrobenzene instead of1-bromo-2,5-difluoro-4-nitrobenzene as starting material. LCMScalculated for C₂₈H₃₀BrFN₅O₄ (M+H)⁺: m/z=598.2; Found: 598.2.

Step 2.N-(2-(1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-4-(2-methylpyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A mixture of tert-butyl(1S,4S)-5-(5-bromo-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(10 mg, 0.017 mmol), (2-methylpyridin-3-yl)boronic acid (4.6 mg, 0.033mmol), XPhosPd G2 (1.3 mg, 1.6 μmol) and potassium phosphate, tribasic(6.7 mg, 0.032 mmol) was combined with 1,4-dioxane (1 mL) and water (0.1 mL). The reaction flask was evacuated, back filled with nitrogen, thenstirred at 80° C. for 1 h. The reaction mixture was cooled to roomtemperature, the solvents were evaporated in vacuo and TFA (1 mL) wasadded. The reaction mixture was stirred at room temperature for 10 min,then diluted with CH₃CN and water and purified with prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min) to provide the TFA salt of thetitle compound. LCMS calculated for C₂₉H₂₈FN₆O₂ (M+H)⁺: m/z=511.2;Found: 511.2. ¹H NMR (600 MHz, DMSO-d₆) δ 10.54-10.46 (s, 1H), 9.33-9.18(d, J=5.0 Hz, 1H), 9.06-8.91 (s, 1H), 8.80-8.74 (s, 1H), 8.67-8.63 (dd,J=5.2, 1.8 Hz, 1H), 8.20-8.14 (d, J=5.0 Hz, 1H), 8.14-8.09 (d, J=8.2 Hz,1H), 8.09-7.98 (d, J=8.1 Hz, 1H), 7.70-7.61 (m, 1H), 7.61-7.55 (td,J=8.4, 6.8 Hz, 1H), 7.31-7.27 (d, J=1.9 Hz, 1H), 7.21-7.15 (dd, J=8.2,1.8 Hz, 1H), 7.12-7.06 (d, J=8.5 Hz, 1H), 7.06-6.96 (t, J=8.8 Hz, 1H),4.39-4.30 (s, 1H), 4.28-4.17 (s, 1H), 3.84-3.71 (s, 3H), 3.62-3.52 (m,1H), 3.39-3.34 (d, J=11.2 Hz, 1H), 3.34-3.28 (m, 1H), 3.15-3.04 (m, 1H),2.63-2.58 (s, 3H), 1.97-1.90 (dd, J=10.8, 2.5 Hz, 1H), 1.84-1.67 (m,1H).

Example 25.N-(2-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-4-(4-methoxypyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 24, using 4-methoxypyridin-3-ylboronicacid instead of (2-methylpyridin-3-yl)boronic acid as starting material.LCMS calculated for C₂₉H₂₈FN₆O₃ (M+H)⁺: m/z=527.2; Found: 527.2.

Example 26.N-(2-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 24, (and detailed below) using3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isonicotinonitrileinstead of (2-methylpyridin-3-yl)boronic acid as starting material.

Step 1. tert-Butyl(1S,4S)-5-(5-bromo-2-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

To a solution of 4-bromo-2-fluoro-1-nitrobenzene (500 mg, 2.3 mmol) andtert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (451 mg,2.3 mmol) in DMSO (8 mL) was added triethylamine (475 μl, 3.41 mmol) andthe reaction mixture was heated to 80° C. for 2 hr.

After cooling to r.t., water was added and the precipitated product wascollected by filtration, washed with water and air dried. It was used inthe next step without further purification. LCMS calculated forC₆₅H₂₁BrN₃O₄(M+H)⁺: m/z=398.1/400.1; found 398.1/400.1.

Step 2. tert-Butyl(1S,4S)-5-(2-amino-5-bromophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

A mixture of tert-butyl(1S,4S)-5-(5-bromo-2-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(914 mg, 2.295 mmol), iron (684 mg, 12.25 mmol) and ammonium chloride(786 mg, 14.70 mmol) in THF (5 mL), water (5 mL) and methanol (5 mL) wasstirred at 60° C. for 3 hrs. After cooling to r.t., it was filteredthrough a plug of Celite and diluted with DCM. The organic phase wasseparated, washed with brine, dried over sodium sulfated and thesolvents were evaporated in vacuo. The obtained crude product was usedin the next step without further purification. LCMS calculated forC₁₆H₂₃BrN₃O₂ (M+H)⁺: m/z=368.1/370.1; Found: 368.1/370.1.

Step 3. tert-Butyl(1S,4S)-5-(5-bromo-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

A solution of tert-butyl(1S,4S)-5-(2-amino-5-bromophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(845 mg, 2.294 mmol),2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid (the product ofExample 1, Step 1, 570 mg, 2.3 mmol) and DIPEA (800 μl, 4.6 mmol) in DMF(5 mL) was treated with HATU (1.3 g, 3.4 mmol). The reaction mixture wasstirred at r.t. for 30 mins, then water was added and the precipitatedproduct was collected by filtration, washed with water and air dried.The crude product was used in the next step without furtherpurification. LCMS calculated for C₂₈H₃₀BrFN₅O₄ (M+H)⁺: m/z=598.2/600.2;Found: 598.2/600.2.

Step 4.N-(2-(1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A mixture of tert-butyl(1S,4S)-5-(5-bromo-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(10 mg, 0.017 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isonicotinonitrile (9.8mg, 0.043 mmol), Xphos Pd G2 (1.3 mg, 1.6 μmol) and potassium phosphate,tribasic (6.7 mg, 0.032 mmol) in 1,4-dioxane (1 mL) and water (0.1 mL)was degassed by evacuation and back filling with nitrogen. The reactionmixture was stirred at 80° C. for 1 hr, cooled to r.t. and the solventswere evaporated in vacuo. TFA (1 mL) was added to the residue and thereaction mixture was stirred at r.t. for 10 min, then diluted with CH₃CNand water and purified with prep-LCMS (XBridge C18 column, eluting witha gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₂₉H₂₅FN₇O₂ (M+H)⁺: m/z=522.2; Found:522.3. ¹H NMR (600 MHz, DMSO-d₆) δ 10.60-10.51 (s, 1H), 9.33-9.22 (d,J=4.9 Hz, 1H), 9.08-9.00 (m, 1H), 9.01-8.95 (s, 1H), 8.88-8.80 (d, J=4.9Hz, 1H), 8.81-8.70 (m, 1H), 8.21-8.15 (d, J=4.9 Hz, 1H), 8.15-8.10 (d,J=8.2 Hz, 1H), 8.06-8.00 (d, J=5.0 Hz, 1H), 7.60-7.53 (q, J=7.9 Hz, 1H),7.53-7.49 (s, 1H), 7.40-7.32 (d, J=8.1 Hz, 1H), 7.13-7.07 (d, J=8.5 Hz,1H), 7.05-6.95 (t, J=8.8 Hz, 1H), 4.42-4.35 (s, 1H), 4.32-4.24 (s, 1H),3.84-3.76 (s, 3H), 3.67-3.58 (d, J=11.0 Hz, 1H), 3.46-3.35 (d, J=10.9Hz, 2H), 3.15-3.04 (dd, J=11.6, 8.2 Hz, 1H), 1.99-1.92 (d, J=10.8 Hz,1H), 1.89-1.75 (d, J=10.7 Hz, 1H).

Example 27.N-(2-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 24, using1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleinstead of (2-methylpyridin-3-yl)boronic acid as starting material. LCMScalculated for C₂₉H₃₁FN₇O₂ (M+H)⁺: m/z=528.2; Found: 528.2.

Example 28.N-(2-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-4-morpholinophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A mixture of tert-butyl(1S,4S)-5-(5-bromo-4-fluoro-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(from Example 18, 10 mg, 0.016 mmol), morpholine (1.4 mg, 0.016 mmol),RuPhosPd G2 (1.2 mg, 1.6 μmol) and cesium carbonate (10.6 mg, 0.032mmol) was combined with 1,4-dioxane (1 mL). The reaction flask wasevacuated, back filled with nitrogen, and stirred at 100° C. for 3 h.The reaction mixture was cooled to room temperature, the solvents wereevaporated in vacuo and TFA (1 mL) was added. The reaction mixture wasstirred at room temperature for 10 min, then diluted with CH₃CN andwater and purified with prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min) to provide the TFA salt of the title compound. LCMS calculatedfor C₂₇H₂₉F₂N₆O₃ (M+H)⁺: m/z=523.2; Found: 523.2.

Example 29.N-(4-(Azetidin-1-yl)-2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 28, using azetidine instead ofmorpholine as starting material. LCMS calculated for C₂₆H₂₇F₂N₆O₂(M+H)⁺: m/z=493.2; Found: 493.2.

Example 30.N-(2-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-4-(morpholinomethyl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. (1S,4S)-tert-Butyl5-(4-fluoro-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-5-formylphenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

Dess-Martin periodinane (269 mg, 0.634 mmol) was added to a solution oftert-butyl(1S,4S)-5-(4-fluoro-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-5-(hydroxymethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(Example 17, 300 mg, 0.529 mmol) and pyridine (51.0 μl, 0.63 mmol) indichloromethane (5 mL). After stirring at room temperature for 1 h, thesolvent was evaporated in vacuo and the crude product was purified byBiotageIsolera™. LCMS calculated for C₂₉H₃₀F₂N₅O₅ (M+H)⁺ m/z=566.2;found 566.3.

Step 2.N-(2-(1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-4-(morpholinomethyl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Sodium triacetoxyborohydride (7.5 mg, 0.035 mmol) was added to asolution of morpholine (1.5 mg, 0.018 mmol), acetic acid (2 μl, 0.035mmol) and tert-butyl(1S,4S)-5-(4-fluoro-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-5-formylphenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(10 mg, 0.018 mmol) in dichloroethane (1 mL). The reaction mixture wasstirred at room temperature for 2 h, and then treated with water. Theaqueous phase was extracted with ethyl acetate, and the combined organicphases were washed with brine, dried over sodium sulfate andconcentrated. The crude residue was taken up in TFA (1 mL) and thereaction was stirred at room temperature for 30 min. The reactionmixture was then diluted with acetonitrile and purified with prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min) to provide the TFA saltof the title compound. LCMS calculated for C₂₈H₃₁F₂N₆O₃ (M+H)⁺:m/z=537.2; Found: 537.3.

Example 31.N-(2-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-4-((cyclobutylamino)methyl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 30, using cyclobutanamine instead ofmorpholine as starting material. LCMS calculated for C₂₈H₃₁F₂N₆O₂(M+H)⁺: m/z=521.2; Found: 521.2.

Example 32.N-(2-((1R,4R)-5-Ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Sodium triacetoxyborohydride (10 mg, 0.046 mmol) was added to a solutionof acetaldehyde (1 mg, 0.023 mmol), acetic acid (2 μl, 0.035 mmol)and/V-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide(from Example 1; 10 mg, 0.023 mmol) in dichloroethane (1 mL). After thereaction mixture was stirred at room temperature for 2 h, it was dilutedwith acetonitrile and purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min) to provide the TFA salt of the title compound.LCMS calculated for C₂₅H₂₆F₂N₅O₂ (M+H)⁺: m/z=466.2; Found: 466.3.

Example 33.N-(5-Fluoro-2-((1R,4R)-5-(2-hydroxyethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Sodium triacetoxyborohydride (10 mg, 0.046 mmol) was added to a solutionof 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (3.98 mg, 0.023 mmol),acetic acid (2 μl, 0.035 mmol) andN-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide(from Example 1; 10 mg, 0.023 mmol) in dichloroethane (1 mL). After thereaction mixture was stirred at room temperature for 2 h, the solventwas evaporated in vacuo and 4 M HCl solution in dioxane (1 mL) was addedto the residue. After additional stirring at room temperature for 1 h,the reaction mixture was diluted with acetonitrile and purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toprovide the TFA salt of the title compound. LCMS calculated forC₂₅H₂₆F₂N₅O₃ (M+H)⁺: m/z=482.2; Found: 482.2.

Example 34.(1R,4R)-5-(4-Fluoro-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)-N-propyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide

Triphosgene (4.1 mg, 0.014 mmol) was added to a solutionof/V-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide(from Example 1, 6 mg, 0.014 mmol) and triethylamine (4 μl, 0.027 mmol)in THF (1 mL). After the reaction mixture was stirred at roomtemperature for 30 min, propan-1-amine (1.2 mg, 0.021 mmol) was addedand the mixture was stirred at room temperature for an additional 30min. The reaction mixture was then diluted with acetonitrile andpurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toprovide the TFA salt of the title compound. LCMS calculated forC₂₇H₂₉F₂N₆O₃ (M+H)⁺: m/z=523.2; Found: 523.3.

Example 35.N-(2-((1R,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-5-methoxyphenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 1, using1-fluoro-4-methoxy-2-nitrobenzene instead of 1,4-difluoro-2-nitrobenzeneas starting material. LCMS calculated for C₂₄H₂₅FN₅O₃ (M+H)⁺: m/z=450.2;Found: 450.3.

Example 36.N-(2-((1R,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-5-(hydroxymethyl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 1, using(4-fluoro-3-nitrophenyl)methanol instead of 1,4-difluoro-2-nitrobenzeneas starting material. LCMS calculated for C₂₄H₂₅FN₅O₃ (M+H)⁺: m/z=450.2;Found: 450.3.

Example 37.N-(2-((1R,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-5-cyanophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 1, using 4-fluoro-3-nitrobenzonitrileinstead of 1,4-difluoro-2-nitrobenzene as starting material. LCMScalculated for C₂₄H₂₂FN₆O₂ (M+H)⁺: m/z=445.2; Found: 445.1.

Example 38.N-(4-(Azetidin-1-yl)-2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 28 and 29, usingA-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-bromophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideinstead ofN-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-bromo-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideas starting material. LCMS calculated for C₂₆H₂₈FN₆O₂ (M+H)⁺: m/z=475.2;Found: 475.2. (500 MHz, DMSO-d₆) δ 10.17-10.04 (s, 1H), 9.27-9.16 (d,J=5.0 Hz, 1H), 8.15-8.04 (d, J=5.1 Hz, 1H), 7.83-7.71 (d, J=8.3 Hz, 1H),7.59-7.48 (td, J=8.4, 6.6 Hz, 1H), 7.10-7.02 (d, J=8.5 Hz, 1H),7.02-6.96 (t, J=8.8 Hz, 1H), 6.07-5.95 (m, 2H), 3.89-3.83 (s, 1H),3.81-3.72 (m, 7H), 3.49-3.44 (s, 1H), 3.38-3.25 (m, 1H), 3.00-2.89 (m,2H), 2.71-2.63 (d, J=9.7 Hz, 1H), 2.34-2.23 (q, J=7.1 Hz, 2H), 1.64-1.57(d, J=9.1 Hz, 1H), 1.52-1.38 (d, J=9.0 Hz, 1H) ppm.

Example 39.N-(2-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-4-((A)-2-(methoxymethyl)azetidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 38, using (S)-2-(methoxymethyl)azetidine instead of azetidine asstarting material. LCMS calculated for C₂₈H₃₂FN₆O₃ (M+H)⁺: m/z=519.2;Found: 519.3. ¹H NMR (500 MHz, DMSO-d₆) δ 10.18-9.96 (s, 1H), 9.28-9.11(d, J=5.0 Hz, 1H), 8.15-8.01 (d, J=5.0 Hz, 1H), 7.79-7.67 (d, J=8.5 Hz,1H), 7.60-7.37 (td, J=8.4, 6.8 Hz, 1H), 7.10-7.02 (d, J=8.4 Hz, 1H),7.02-6.91 (m, 1H), 6.41-6.27 (d, J=2.4 Hz, 1H), 6.19-6.04 (dd, J=8.7,2.4 Hz, 1H), 4.14-4.05 (dd, J=7.6, 3.6 Hz, 1H), 3.87-3.79 (m, 3H),3.79-3.74 (s, 3H), 3.67-3.58 (dd, J=10.3, 6.7 Hz, 1H), 3.58-3.46 (m,3H), 3.40-3.27 (m, 4H), 3.04-2.90 (m, 2H), 2.74-2.60 (dd, J=9.7, 2.2 Hz,1H), 2.32-2.21 (m, 1H), 2.17-2.05 (dq, J=10.8, 8.3 Hz, 1H), 1.68-1.57(d, J=9.1 Hz, 1H), 1.56-1.47 (m, 1H) ppm.

Example 40.N-(2-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-4-(3-cyanopyridin-4-yl)-3-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. (1S,4S)-tert-Butyl5-(3-bromo-2-fluoro-6-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

This compound was prepared according to the procedures described inExample 18, using 1-bromo-2,3-difluoro-4-nitrobenzene instead of1-bromo-2,5-difluoro-4-nitrobenzene as starting material. LCMScalculated for C₂₈H₂₉BrF₂N₅O₄ (M+H)⁺: m/z=616.1; Found: 616.1.

Step 2.N-(2-(1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-4-(3-cyanopyridin-4-yl)-3-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A mixture of tert-butyl(1S,4S)-5-(3-bromo-2-fluoro-6-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(10 mg, 0.016 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (10 mg,0.043 mmol), Xphos Pd G2 (1.3 mg, 1.6 μmol) and potassium phosphate,tribasic (6.7 mg, 0.032 mmol) was combined with 1,4-dioxane (1 ml) andwater (0.1 ml). The reaction mixture was degassed under vacuum, backfilled with nitrogen and then stirred at 80° C. for 1 h. The reactionmixture was cooled to room temperature, the solvents were concentratedand TFA (1 ml) was added. The reaction mixture was stirred at roomtemperature for 10 min, then diluted with CH₃CN and water and purifiedwith prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₉H₂₄F₂N₇O₂ (M+H)⁺: m/z=540.2; Found: 540.1. ¹H NMR (500MHz, DMSO-d₆) δ 10.94-10.84 (s, 1H), 9.37-9.27 (d, J=5.0 Hz, 1H),9.20-9.11 (s, 1H), 9.07-8.99 (br, 1H), 8.98-8.94 (d, J=5.2 Hz, 1H),8.81-8.72 (br, 1H), 8.44-8.37 (d, J=8.6 Hz, 1H), 8.27-8.16 (d, J=5.0 Hz,1H), 7.79-7.75 (d, J=5.2 Hz, 1H), 7.62-7.56 (td, J=8.5, 6.9 Hz, 1H),7.56-7.51 (t, J=8.1 Hz, 1H), 7.12-7.06 (d, J=8.5 Hz, 1H), 7.05-6.97 (m,1H), 4.46-4.34 (m, 1H), 4.15-4.08 (s, 1H), 3.82-3.74 (s, 3H), 3.62-3.54(d, J=10.7 Hz, 1H), 3.49-3.41 (m, 1H), 3.41-3.33 (m, 1H), 3.17-3.07 (m,1H), 1.95-1.88 (d, J=10.6 Hz, 1H), 1.68-1.58 (m, 1H) ppm.

Example 41.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(3-cyanopyridin-4-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. tert-Butyl(3S,5S)-1-(5-bromo-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate

This compound was prepared according to the procedures described inExample 22 and 1, using tert-butyl(3S,5S)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate instead of(1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate asstarting material. LCMS calculated for C₂₈H₃₂BrFN₅O₅(M+H)⁺: m/z=616.2;Found: 616.2.

Step 2.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(3-cyanopyridin-4-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A mixture of tert-butyl((3S,5S)-1-(5-bromo-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(10 mg, 0.016 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (9.8 mg,0.043 mmol), Xphos Pd G2 (1.3 mg, 1.6 μmol) and potassium phosphate,tribasic (6.7 mg, 0.032 mmol) was combined with 1,4-dioxane (1 ml) andwater (0.1 ml). The reaction mixture was degassed under vacuum, backfilled with nitrogen, then stirred at 80° C. for 1 h. The reactionmixture was cooled to room temperature, the solvents were concentratedand TFA (1 ml) was added. The reaction mixture was stirred at roomtemperature for 10 min, then diluted with CH₃CN and water and purifiedwith prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₉H₂₇FN₇O₃ (M+H)⁺: m/z=540.2; Found: 540.1. ¹H NMR (600MHz, DMSO-d₆) δ 10.69-10.61 (s, 1H), 9.32-9.25 (d, J=5.0 Hz, 1H),9.14-9.04 (s, 1H), 8.94-8.86 (d, J=5.3 Hz, 1H), 8.35-8.28 (d, J=8.4 Hz,1H), 8.22-8.13 (d, J=5.0 Hz, 1H), 7.97-7.85 (d, J=5.5 Hz, 2H), 7.81-7.75(d, J=5.4 Hz, 1H), 7.73-7.68 (d, J=2.1 Hz, 1H), 7.60-7.53 (td, J=8.4,6.8 Hz, 1H), 7.53-7.47 (dd, J=8.4, 2.0 Hz, 1H), 7.11-7.05 (d, J=8.5 Hz,1H), 7.04-6.96 (t, J=8.8 Hz, 1H), 3.89-3.81 (m, 1H), 3.79-3.76 (s, 3H),3.76-3.68 (m, 1H), 3.44-3.29 (m, 3H), 3.27-3.22 (dd, J=11.1, 2.6 Hz,1H), 2.43-2.33 (m, 1H), 1.90-1.80 (m, 1H) ppm.

Example 42.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound (free base and TFA salt) was prepared according to theprocedures described in Example 41 (and detailed below), using3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isonicotinonitrileinstead of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile asstarting material.

Step 1. tert-Butyl((3S,5S)-1-(5-bromo-2-nitrophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate

A solution of 4-bromo-2-fluoro-1-nitrobenzene (532 mg, 2.42 mmol) andtert-butyl ((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate (523 mg,2.42 mmol) in DMSO (8 mL) was treated with triethylamine (506 μL, 3.63mmol) and the reaction mixture was heated to 80° C. for 2 hr. Aftercooling to r.t., water was added and the precipitated product wascollected by filtration, washed with water and air dried. It was used inthe next step without further purification. LCMS calculated forC₁₂H₁₅BrN₃O₅(M+H-C₄H₈)⁺: m/z=360.0/362.0; found 360.0/362.0.

Step 2. tert-Butyl((3S,5S)-1-(2-amino-5-bromophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate

A mixture of tert-butyl((3S,5S)-1-(5-bromo-2-nitrophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(1 g, 2.45 mmol), iron (684 mg, 12.25 mmol) and ammonium chloride (786mg, 14.70 mmol) in THF (5 mL), water (5 mL) and methanol (5 mL) wasstirred at 60° C. for 3 hrs. After cooling to r.t., it was filteredthrough a plug of Celite and diluted with DCM. The organic phase wasseparated, washed with saturated aqueous sodium chloride, dried oversodium sulfate and the solvents were evaporated in vacuo. The obtainedcrude product was used in the next step without further purification.LCMS calculated for C₁₆H₂₅BrN₃O₃ (M+H)⁺: m/z=386.1/388.1; Found:386.1/388.1.

Step 3. tert-Butyl((3S,5S)-1-(5-bromo-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate

HATU (1196 mg, 3.15 mmol) was added to a solution of tert-butyl(3S,5S)-1-(2-amino-5-bromophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(810 mg, 2.097 mmol),2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid (the product ofExample 1, step 1, 520 mg, 2.097 mmol) and DIPEA (732 μl, 4.19 mmol) inDMF (5 mL). The reaction mixture was stirred at r.t. for 30 mins, thenwater was added and the precipitated product was collected byfiltration, washed with water and air dried. The solid was used in thenext step without further purification. LCMS calculated forC₂₈H₃₂BrFN₅O₅(M+H)⁺: m/z=616.2/618.2; Found: 616.2/618.2.

Step 4.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A mixture of tert-butyl(3S,5S)-1-(5-bromo-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(10 mg, 0.016 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isonicotinonitrile (9.8mg, 0.043 mmol), Xphos Pd G2 (1.3 mg, 1.6 μmol) and potassium phosphate,tribasic (6.7 mg, 0.032 mmol) was combined with 1,4-dioxane (1 mL) andwater (0.1 mL) and the reaction flask was evacuated, back filled withnitrogen, then stirred at 80° C. for 1 hr. The reaction mixture wascooled to r.t., the solvents were evaporated in vacuo and TFA (1 mL) wasadded. The reaction mixture was stirred at r.t. for 10 min, then dilutedwith CH₃CN and water and purified with prep-LCMS. LCMS calculated forC₂₉H₂₇FN₇O₃ (M+H)⁺: m/z=540.2; Found: 540.1. Prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%NH₄OH, at flow rate of 60 mL/min). Free base: ¹H NMR (500 MHz, DMSO-d6)δ 9.33-9.25 (d, J=5.0 Hz, 1H), 8.98-8.93 (s, 1H), 8.84-8.78 (d, J=5.0Hz, 1H), 8.46-8.39 (d, J=8.4 Hz, 1H), 8.22-8.18 (d, J=5.0 Hz, 1H),8.00-7.92 (dd, J=5.1, 0.7 Hz, 1H), 7.67-7.64 (m, 1H), 7.59-7.52 (td,J=8.4, 6.8 Hz, 1H), 7.48-7.43 (dd, J=8.3, 2.1 Hz, 1H), 7.11-7.04 (d,J=8.5 Hz, 1H), 7.03-6.90 (t, J=8.8 Hz, 1H), 3.85-3.73 (s, 3H), 3.68-3.56(m, 1H), 3.39-3.29 (m, 3H), 3.28-3.22 (d, J=4.8 Hz, 1H), 3.06-2.97 (d,J=5.4 Hz, 1H), 2.31-2.18 (dt, J=12.6, 7.5 Hz, 1H), 1.40-1.29 (dt,J=12.7, 6.2 Hz, 1H) ppm. Prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). TFA salt: ¹H NMR (500 MHz, DMSO-76) δ 10.66-10.59 (s, 1H),9.31-9.24 (d, J=5.0 Hz, 1H), 9.03-8.94 (d, J=0.8 Hz, 1H), 8.88-8.78 (d,J=5.0 Hz, 1H), 8.34-8.24 (d, J=8.4 Hz, 1H), 8.24-8.17 (d, J=5.0 Hz, 1H),8.04-7.95 (dd, J=5.1, 0.8 Hz, 1H), 7.92-7.82 (br, J=5.5 Hz, 2H),7.73-7.65 (d, J=2.0 Hz, 1H), 7.61-7.54 (td, J=8.5, 6.9 Hz, 1H),7.50-7.45 (dd, J=8.4, 2.0 Hz, 1H), 7.11-7.05 (d, J=8.5 Hz, 1H),7.05-6.98 (t, J=8.8 Hz, 1H), 3.89-3.82 (m, 1H), 3.81-3.77 (s, 3H),3.76-3.69 (m, 1H), 3.42-3.21 (m, 4H), 2.43-2.31 (m, 1H), 1.90-1.77 (dt,J=13.2, 5.3 Hz, 1H) ppm.

Example 43.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(2-methylpyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 41, using (2-methylpyridin-3-yl)boronic acid instead of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile asstarting material. LCMS calculated for C₂₉H₃₀FN₆O₃ (M+H)⁺: m/z=529.2;Found: 529.2. ¹H NMR (500 MHz, DMSO-d₆) δ 10.69-10.55 (s, 1H), 9.33-9.17(d, J=5.0 Hz, 1H), 8.72-8.62 (dd, J=5.4, 1.7 Hz, 1H), 8.31-8.20 (d,J=8.3 Hz, 1H), 8.23-8.15 (d, J=5.0 Hz, 1H), 8.14-8.05 (d, J=7.6 Hz, 1H),8.05-7.86 (br, J=5.4 Hz, 2H), 7.75-7.64 (dd, J=7.7, 5.4 Hz, 1H),7.62-7.52 (td, J=8.4, 6.8 Hz, 1H), 7.47-7.41 (d, J=2.0 Hz, 1H),7.31-7.23 (dd, J=8.3, 1.9 Hz, 1H), 7.11-7.05 (d, J=8.5 Hz, 1H),7.05-6.95 (t, J=8.8 Hz, 1H), 3.87-3.76 (m, 4H), 3.76-3.66 (m, 1H),3.42-3.20 (m, 4H), 2.65-2.57 (s, 3H), 2.43-2.32 (dt, J=13.2, 7.9 Hz,1H), 1.91-1.65 (dt, J=13.3, 5.5 Hz, 1H) ppm.

Example 44.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(3-methoxypyridin-4-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 41, using (3-methoxypyridin-4-yl)boronic acid instead of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile asstarting material. LCMS calculated for C₂₉H₃₀FN₆O₄ (M+H)⁺: m/z=545.2;Found: 545.3. ¹H NMR (500 MHz, DMSO-d₆) δ 10.66-10.59 (s, 1H), 9.30-9.25(d, J=5.0 Hz, 1H), 8.55-8.48 (s, 1H), 8.39-8.33 (d, J=5.0 Hz, 1H),8.28-8.21 (d, J=8.4 Hz, 1H), 8.21-8.16 (d, J=5.0 Hz, 1H), 7.92-7.81 (br,2H), 7.63-7.59 (m, 1H), 7.59-7.55 (m, 1H), 7.55-7.51 (m, 1H), 7.48-7.44(dd, J=8.4, 1.9 Hz, 1H), 7.14-7.11 (s, 1H), 7.09-7.05 (d, J=8.5 Hz, 1H),7.01-6.96 (d, J=8.8 Hz, 1H), 3.99-3.90 (s, 3H), 3.83-3.73 (m, 4H),3.73-3.67 (m, 1H), 3.40-3.19 (m, 4H), 2.44-2.35 (m, 1H), 1.88-1.79 (dt,J=13.3, 5.2 Hz, 1H) ppm.

Example 45.N-(3-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2′-cyano-6′-fluorobiphenyl-4-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 41, using3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrileinstead of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile asstarting material. LCMS calculated for C₃₀H₂₇F₂N₆O₃ (M+H)⁺: m/z=557.2;Found: 557.1.

Example 46.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(3-cyanopyridin-2-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. tert-Butyl(3S,5S)-1-(2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate

1,4-Dioxane (10 ml) was added to a mixture of4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (412 mg,1.6 mmol), potassium acetate (159 mg, 1.6 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexedwith dichloromethane (1:1) (66.2 mg, 0.081 mmol) and tert-butyl((3S,5S)-1-(5-bromo-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(500 mg, 0.811 mmol). The reaction mixture was degassed under vacuum,back filled with nitrogen, and stirred at 100° C. overnight. Thereaction mixture was then cooled to room temperature, filtered through aplug of Celite and the solvent concentrated under vacuum. The crudematerial was purified by Biotage Isolera to give yellow solid (300 mg,56%). LCMS calculated for C₃₄H₄₄BFN₅O₇ (M+H)⁺: m/z=664.3; Found: 664.3.

Step 2.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(3-cyanopyridin-2-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A mixture of tert-butyl((3S,5S)-1-(2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(10 mg, 0.015 mmol), 2-bromonicotinonitrile (5.52 mg, 0.030 mmol), XphosPd G2 (1.3 mg, 1.6 μmol) and potassium phosphate, tribasic (6.7 mg,0.032 mmol) was combined with 1,4-dioxane (1 ml) and water (0.1 ml). Thereaction mixture was degassed under vacuum, back filled with nitrogenand then stirred at 80° C. for 1 h. The reaction mixture was cooled toroom temperature, the solvents were concentrated and TFA (1 ml) wasadded. The reaction mixture was stirred at room temperature for 10 min,then diluted with CH₃CN and water and purified with prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C₂₉H₂₇FN₇O₃(M+H)⁺: m/z=540.2; Found: 540.1. ¹H NMR (500 MHz, DMSO-d6) δ 10.71-10.58(s, 1H), 9.35-9.21 (d, J=5.0 Hz, 1H), 8.97-8.91 (dd, J=4.8, 1.7 Hz, 1H),8.49-8.40 (dd, J=7.9, 1.7 Hz, 1H), 8.39-8.30 (d, J=8.4 Hz, 1H),8.26-8.16 (d, J=5.0 Hz, 1H), 7.96-7.82 (m, 3H), 7.75-7.70 (dd, J=8.4,2.0 Hz, 1H), 7.66-7.60 (dd, J=7.9, 4.9 Hz, 1H), 7.60-7.52 (td, J=8.4,6.8 Hz, 1H), 7.11-7.05 (d, J=8.5 Hz, 1H), 7.04-6.97 (t, J=8.8 Hz, 1H),3.87-3.76 (m, 4H), 3.75-3.69 (m, 1H), 3.46-3.15 (m, 4H), 2.44-2.33 (m,1H), 1.91-1.76 (m, 1H) ppm.

Example 47.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyano-1-methyl-1H-pyrazol-5-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 46, using 5-bromo-1-methyl-1H-pyrazole-4-carbonitrile instead of2-bromonicotinonitrile as starting material. LCMS calculated forC₂₈H₂₈FN₈O₃ (M+H)⁺: m/z=543.2; Found: 543.2.

Example 48.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-isopropylphenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. tert-Butyl(3S,5S)-1-(2-(2-(2-Fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-5-(prop-1-en-2-yl)phenyl)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate

This compound was prepared according to the procedures described inExample 41, using4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane instead of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile asstarting material. LCMS calculated for C₃₁H₃₇FN₅O₅ (M+H)⁺: m/z=578.3;Found: 578.3.

Step 2.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-isopropylphenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Palladium on carbon (10w %, 18.42 mg, 0.017 mmol) was added to asolution of tert-butyl((3S,5S)-1-(2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-5-(prop-1-en-2-yl)phenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(100 mg, 0.173 mmol) in methanol (6 ml). The reaction mixture wasstirred at room temperature for 5 h under an atmosphere of hydrogen. Thecatalyst was filtered off, the solvent was concentrated and TFA (1 ml)was added. The reaction mixture was stirred at room temperature for 10min, then diluted with CH₃CN and water and purified with prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated forC₂₆H₃₁FN₅O₃ (M+H)⁺: m/z=480.2; Found: 480.2. ¹H NMR (500 MHz, DMSO-d₆) δ10.50-10.37 (s, 1H), 9.33-9.20 (d, J=5.0 Hz, 1H), 8.18-8.07 (d, J=5.0Hz, 1H), 8.07-8.02 (d, J=8.3 Hz, 1H), 7.88-7.73 (br, J=5.7 Hz, 2H),7.61-7.47 (td, J=8.4, 6.8 Hz, 1H), 7.27-7.18 (s, 1H), 7.14-7.03 (dd,J=8.4, 1.9 Hz, 2H), 7.03-6.94 (t, J=8.8 Hz, 1H), 3.81-3.73 (s, 3H),3.75-3.66 (m, 1H), 3.33-3.12 (m, 4H), 2.95-2.81 (p, J=6.9 Hz, 1H),2.45-2.33 (m, 1H), 1.87-1.67 (dt, J=13.2, 5.0 Hz, 1H), 1.24-1.17 (d,J=6.9 Hz, 6H) ppm. Example 49.N-(4-(3-Cyanopyridin-4-yl)-2-((2S,4S)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 41, using (35′,55′)-5-(hydroxymethyl)pyrrolidin-3-ol instead oftert-butyl (3S,5S)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate as startingmaterial. LCMS calculated for C₂₉H₂₆FN₆O₄ (M+H)⁺: m/z=541.2; Found:541.2.

Intermediate 1. 3-(3-Fluoro-4-nitrophenyl)isonicotinonitrile

A mixture of3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isonicotinonitrile (1 g,4.34 mmol), 4-bromo-2-fluoro-1-nitrobenzene (637 mg, 2.90 mmol), XPhosPd G2 (228 mg, 0.29 mmol), and potassium phosphate, tribasic (1.23 g,5.79 mmol) was combined with dioxane (88 mL) and water (8.8 mL). Thereaction mixture was degassed under vacuum, back filled with nitrogenand then stirred at 80° C. for 16 h. After cooling to room temperature,the mixture was filtered through Celite and washed with ethyl acetate,followed by concentrating under vacuum. The residue was then purified byBiotage Isolera to give 3-(3-fluoro-4-nitrophenyl)isonicotinonitrile asa tan solid (550 mg, 78% yield). LCMS calculated for C₁₂H₇FN₃O₂ (M+H)⁺:m/z=244.0; found 244.0.

Example 50.N-(4-(4-Cyanopyridin-3-yl)-2-((2S,5R)-2-(hydroxymethyl)-5-methylpiperazin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. (2R,5S)-tert-Butyl4-(5-(4-cyanopyridin-3-yl)-2-nitrophenyl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate

A solution of 3-(3-fluoro-4-nitrophenyl)isonicotinonitrile (Intermediate1, 52.8 mg, 0.22 mmol) and (2R,5S)-tert-butyl5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate (50 mg, 0.22 mmol;prepared by an adaptation of the procedure described in: Chessari, G. etal. J. Med. Chem. 2015, 55, 6574-6588) in DMSO (724 μL) was treated withtriethylamine (45.4 μL, 0.33 mmol) and the reaction mixture was heatedto 100° C. for 16 h. After cooling to room temperature, the reactionmixture was diluted with CH₂Cl₂, washed with brine, dried over MgSO₄,filtered and concentrated under vacuum. The crude product was used inthe next reaction without purification. LCMS calculated for C₂₃H₂₈N₅O₅(M+H)⁺: m/z=454.2; found 454.2.

Step 2. (2R,5S)-tert-Butyl4-(2-amino-5-(4-cyanopyridin-3-yl)phenyl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate

A mixture of (2S,5S)-tert-butyl4-(5-(4-cyanopyridin-3-yl)-2-nitrophenyl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate(98 mg, 0.22 mmol), iron (60 mg, 1.08 mmol) and ammonium chloride (69mg, 1.30 mmol) in THF (2 mL), water (2 mL) and methanol (2 mL) wasstirred at 60° C. for 1 h. After cooling to room temperature, thereaction mixture was filtered through a plug of Celite and diluted withCH₂Cl₂. The organic phase was separated, washed with brine, dried overMgSO₄, filtered and concentrated under vacuum. The crude product wasused in the next step without further purification. LCMS calculated forC₂₃H₃₀N₅O₃ (M+H)⁺: m/z=424.2; Found: 424.2.

Step 3.N-(4-(4-Cyanopyridin-3-yl)-2-((2S,5R)-2-(hydroxymethyl)-5-methylpiperazin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

HATU (124 mg, 0.326 mmol) was added to a solution of (2S,5S)-tert-butyl4-(2-amino-5-(4-cyanopyridin-3-yl)phenyl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate(92 mg, 0.22 mmol), 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylicacid (54 mg, 0.22 mmol) and DIPEA (76 μL, 0.43 mmol) in DMF (510 μL).The reaction mixture was stirred at 60° C. for 30 min and then treatedwith water. The precipitated product was collected by filtration, washedwith water and air dried. It was then redissolved in TFA and thesolution was stirred at 60° C. for 10 min. After cooling, the solventwas concentrated under vacuum and the crude residue was dissolved in THF(1 mL), MeOH (1 mL), and aq. NH₄OH (1 mL). The reaction mixture wasstirred at 60° C. for 30 min in a sealed container. The mixture wascooled, the solvent concentrated under vacuum and the resultant residuewas diluted with acetonitrile and purified with prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). C₃₀H₂₉FN₇O₃ (M+H)⁺: m/z=554.2; found554.3.

Example 51.N-(4-(4-Cyanopyridin-3-yl)-2-((2S,5S)-2-(hydroxymethyl)-5-methylpiperazin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 50, using 2S,5S)-tert-butyl5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate instead of(2R,5S)-tert-butyl 5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate asstarting material. LCMS calculated for C₃₀H₂₉FN₇O₃ (M+H)⁺: m/z=554.2;Found: 554.1.

Example 52.(S)—N-(4-(4-Cyanopyridin-3-yl)-2-(6-(hydroxymethyl)-4,7-diazaspiro[2.5]octan-7-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 50, using (S)-tert-butyl6-(hydroxymethyl)-4,7-diazaspiro[2.5]octane-4-carboxylate instead of(2R,5S)-tert-butyl 5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate asstarting material. LCMS calculated for C₃₁H₂₉FN₇O₃ (M+H)⁺: m/z=566.2;Found: 566.2.

Example 53.N-(2-((2S,4S)-4-Amino-2-(1-hydroxycyclopropyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. (2S,4S)-1-Benzyl 2-methyl4-(tert-butoxycarbonylamino)pyrrolidine-1,2-dicarboxylate

A solution of (2S,4S)-methyl4-(tert-butoxycarbonylamino)pyrrolidine-2-carboxylate (250 mg, 1.02mmol) and DIPEA (536 μL, 3.07 mmol) in CH₂Cl₂ (6.4 mL) at 0° C. wastreated with benzyl chloroformate (175 μL, 1.23 mmol) and the reactionmixture was left to stir for 1 h. The reaction mixture was treated withsat. aq. NaHCO₃ and diluted with CH₂Cl₂, washed with brine, dried overMgSO₄, filtered and concentrated. The crude product was used in the nextreaction without purification. LCMS calculated for C₁₉H₂₇N₂O₆ (M+H)⁺:m/z=379.2; found 379.1.

Step 2. (2S,4S)-Benzyl4-(tert-butoxycarbonylamino)-2-(1-hydroxycyclopropyl)pyrrolidine-1-carboxylate

A solution of (2S,4S)-1-benzyl 2-methyl4-(tert-butoxycarbonylamino)pyrrolidine-1,2-dicarboxylate (100 mg, 0.26mmol) and titanium isopropoxide (16 μL, 0.053 mmol) in THF (755 μL) at0° C. was treated with ethylmagnesium bromide (1M in THF, 1.06 mL, 1.06mmol) and the reaction mixture was stirred at room temperature for 1 h.The reaction mixture was then treated with sat. aq. NH₄Cl and dilutedwith EtOAc. The separated organic phase was washed with brine, driedover MgSO₄, filtered and concentrated. The crude product was used in thenext reaction without purification. LCMS calculated for C₂₀H₂₉N₂O₅(M+H)⁺: m/z=377.2; found 377.1.

Step 3. tert-Butyl(3S,5S)-5-(1-hydroxycyclopropyl)pyrrolidin-3-ylcarbamate

A Parr reaction vessel was charged with (2S,4S)-benzyl4-(tert-butoxycarbonylamino)-2-(1-hydroxycyclopropyl)pyrrolidine-1-carboxylate(99 mg, 0.26 mmol), Pd/C (10% wetted, Degussa type, 28 mg) followed byMeOH (10.5 mL). The reaction mixture was evacuated and backfilled 3×with nitrogen gas, followed by another evacuation cycle and thenpressurized with hydrogen gas to 25 psi. The reaction vessel wasagitated overnight. The reaction mixture was then filtered over Celiteand the solvent concentrated under vacuum. The crude product was used inthe next reaction without purification. LCMS calculated for C₁₂H₂₂N₂O₂(M+H)⁺: m/z=243.2; found 243.3.

Step 4. tert-Butyl(3S,5S)-1-(5-(4-cyanopyridin-3-yl)-2-nitrophenyl)-5-(I-hydroxycyclopropyl)pyrrolidin-3-ylcarbamate

A solution of 3-(3-fluoro-4-nitrophenyl)isonicotinonitrile (Intermediate1, 64 mg, 0.26 mmol) and tert-butyl(3S,5S)-5-(1-hydroxycyclopropyl)pyrrolidin-3-ylcarbamate (64 mg, 0.26mmol) in DMSO (880 μL) was treated with triethylamine (55 μL, 0.40 mmol)and the reaction mixture was heated to 100° C. for 16 h. After coolingto room temperature, the reaction mixture was diluted with CH₂Cl₂,washed with brine, dried over MgSO₄, filtered and the solventconcentrated under vacuum. The crude product was used in the nextreaction without purification. LCMS calculated for C₂₄H₂₈N₅O₅ (M+H)⁺:m/z=466.2; found 466.3.

Step 5. tert-Butyl(3S,5S)-1-(2-amino-5-(4-cyanopyridin-3-yl)phenyl)-5-(1-hydroxycyclopropyl)pyrrolidin-3-ylcarbamate

A mixture of tert-butyl(3S,5S)-5-(1-hydroxycyclopropyl)pyrrolidin-3-ylcarbamate (123 mg, 0.26mmol), iron (74 mg, 1.32 mmol) and ammonium chloride (85 mg, 1.58 mmol)in THF (2 mL), water (2 mL) and methanol (2 mL) was stirred at 60° C.for 1 h. After cooling to room temperature, the mixture was filteredthrough a plug of Celite and diluted with CH₂Cl₂. The organic phase wasseparated, washed with brine, dried over MgSO₄, filtered and thesolvents concentrated under vacuum. The crude product was used in thenext step without further purification. LCMS calculated for C₂₄H₃₀N₅O₃(M+H)⁺: m/z=436.1; Found: 436.2.

Step 6.N-(2-((2S,4S)-4-Amino-2-(I-hydroxycyclopropyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

HATU (151 mg, 0.40 mmol) was added to a solution of tert-butyl(3S,5S)-1-(2-amino-5-(4-cyanopyridin-3-yl)phenyl)-5-(1-hydroxycyclopropyl)pyrrolidin-3-ylcarbamate(115 mg, 0.26 mmol), 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylicacid (65 mg, 0.26 mmol) and DIPEA (92 μL, 0.53 mmol) in DMF (620 μL).The reaction mixture was stirred at 60° C. for 30 min and then treatedwith water. The precipitated product was collected by filtration, washedwith water and air dried. It was redissolved in TFA and the solution wasstirred at 60° C. for 10 min. After cooling, the solvent wasconcentrated and the crude product was then diluted with CH₃CN andpurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₃₁H₂₉FN₇O₃ (M+H)⁺: m/z=566.2; Found: 566.3.

Example 54.N-(2-((2S,4S)-4-Amino-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. tert-Butyl(3S,5S)-5-(2-hydroxypropan-2-yl)pyrrolidin-3-ylcarbamate

A solution of (2S,4S)-methyl4-(tert-butoxycarbonylamino)pyrrolidine-2-carboxylate (100 mg, 0.41mmol) in THF (4.1 mL) at 0° C. was treated with methylmagnesium bromide(3M in THF, 546 μL, 1.64 mmol) and the reaction mixture was stirred atroom temperature for 1 h.

The reaction mixture was treated with sat. aq. NH₄Cl and diluted withEtOAc. The separated organic phase was washed with brine, dried overMgSO₄, filtered and concentrated under vacuum. The crude product wasused in the next reaction without purification. LCMS calculated forC₁₂H₂₅N₂O₃ (M+H)⁺: m/z=245.2; found 245.2.

Step 2. tert-Butyl(3S,5S)-1-(5-(4-cyanopyridin-3-yl)-2-nitrophenyl)-5-(2-hydroxypropan-2-yl)pyrrolidin-3-ylcarbamate

A solution of 3-(3-fluoro-4-nitrophenyl)isonicotinonitrile (Intermediate1, 50 mg, 0.20 mmol) and tert-butyl(3S,5S)-5-(2-hydroxypropan-2-yl)pyrrolidin-3-ylcarbamate (50 mg, 0.20mmol) in DMSO (680 μL) was treated with triethylamine (43 μL, 0.31 mmol)and the reaction mixture was heated to 100° C. for 16 h. After coolingto room temperature, the reaction mixture was diluted with CH₂Cl₂,washed with brine, dried over MgSO₄, filtered and concentrated undervacuum. The crude product was used in the next reaction withoutpurification. LCMS calculated for C₂₄H₃₀N₅O₅ (M+H)⁺: m/z=468.2; found468.1.

Step 3. tert-Butyl(3S,5S)-1-(2-amino-5-(4-cyanopyridin-3-yl)phenyl)-5-(2-hydroxypropan-2-yl)pyrrolidin-3-ylcarbamate

A mixture of tert-butyl(3S,5S)-1-(5-(4-cyanopyridin-3-yl)-2-nitrophenyl)-5-(2-hydroxypropan-2-yl)pyrrolidin-3-ylcarbamate(96 mg, 0.20 mmol), iron (57 mg, 1.03 mmol) and ammonium chloride (66mg, 1.23 mmol) in THF (2 mL), water (2 mL) and methanol (2 mL) wasstirred at 60° C. for 1 h. After cooling to room temperature, themixture was filtered through a plug of Celite and diluted with CH₂Cl₂.The organic phase was separated, washed with brine, dried over MgSO₄,filtered and the solvents were concentrated under vacuum. The crudeproduct was used in the next step without further purification. LCMScalculated for C₂₄H₃₂N₅O₃ (M+H)⁺: m/z=438.2; Found: 438.1.

Step 4.N-(2-((2S,4S)-4-Amino-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

HATU (117 mg, 0.31 mmol) was added to a solution of tert-butyl(3S,5S)-1-(2-amino-5-(4-cyanopyridin-3-yl)phenyl)-5-(2-hydroxypropan-2-yl)pyrrolidin-3-ylcarbamate(90 mg, 0.21 mmol), 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylicacid (51 mg, 0.21 mmol) and DIPEA (72 μL, 0.41 mmol) in DMF (480 μL).The reaction mixture was stirred at 60° C. for 30 min and then treatedwith water. The precipitated product was collected by filtration, washedwith water and air dried. The solid was dissolved in TFA and theresultant solution was stirred at 60° C. for 10 min. The solution wascooled, concentrated and the crude product was diluted with CH₃CN andpurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₃₁H₃₁FN₇O₃(M+H)⁺: m/z=568.2; Found: 568.3

Example 55.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl-d2)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. tert-Butyl (3S,5S)-5-(hydroxymethyl-d2)pyrrolidin-3-ylcarbamate

A solution of (2S,4S)-methyl4-(tert-butoxycarbonylamino)pyrrolidine-2-carboxylate (100 mg, 0.41mmol) in THF (4.1 mL) at 0° C. was treated with lithium aluminumdeuteride (17 mg, 0.41 mmol) and the reaction mixture was stirred for 1h, then warmed to room temperature and stirred for an additional 30 min.The reaction mixture was diluted with Et₂O, water, and 15% aq. LiOH. Theseparated organic phase was dried over MgSO₄, filtered and the solventconcentrated under vacuum. The crude product was used in the nextreaction without purification. LCMS calculated for C₁₀H₁₉D₂N₂O₃ (M+H)⁺:m/z=219.2; found 219.1.

Step 2. tert-Butyl(3S,5S)-1-(5-(4-cyanopyridin-3-yl)-2-nitrophenyl)-5-(hydroxymethyl-d2)pyrrolidin-3-ylcarbamate

A solution of 3-(3-fluoro-4-nitrophenyl)isonicotinonitrile (Intermediate1, 99 mg, 0.41 mmol) and tert-butyl(3S,5S)-5-(hydroxymethyl-d2)pyrrolidin-3-ylcarbamate (89 mg, 0.41 mmol)in DMSO (1.36 mL) was treated with triethylamine (85 μL, 0.61 mmol) andthe reaction mixture was heated to 100° C. for 16 hrs. After cooling tor.t., the reaction mixture was diluted with CH₂Cl₂, washed with brine,dried over MgSO₄, filtered and the solvent was concentrated. The crudeproduct was used in the next reaction without purification. LCMScalculated for C₂₂H₂₄D₂N₅O₅ (M+H)⁺: m/z=442.2; found 442.1.

Step 3. tert-Butyl(3S,5S)-1-(2-amino-5-(4-cyanopyridin-3-yl)phenyl)-5-(hydroxybiusdeuteromethyl)pyrrolidin-3-ylcarbamate

A mixture of tert-butyl(3S,5S)-1-(5-(4-cyanopyridin-3-yl)-2-nitrophenyl)-5-(hydroxymethyl-d2)pyrrolidin-3-ylcarbamate(180 mg, 2.04 mmol), iron (114 mg, 1.03 mmol) and ammonium chloride (131mg, 2.45 mmol) in THF (2 mL), water (2 mL) and methanol (2 mL) wasstirred at 60° C. for 1 h. After cooling to room temperature, themixture was filtered through a plug of Celite and diluted with CH₂Cl₂.The organic phase was separated, washed with brine, dried over MgSO₄,filtered and the solvents concentrated. The crude product was used inthe next step without further purification. LCMS calculated forC₂₂H₂₆D2N₅O₃ (M+H)⁺: m/z=412.2; Found: 412.2.

Step 4.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl-d2)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

HATU (233 mg, 0.61 mmol) was added to a solution of tert-butyl(3S,5S)-1-(2-amino-5-(4-cyanopyridin-3-yl)phenyl)-5-(hydroxymethyl-d2)pyrrolidin-3-ylcarbamate(168 mg, 0.41 mmol), 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylicacid (101 mg, 0.41 mmol) and DIPEA (143 μL, 0.82 mmol) in DMF (956 μL).The reaction mixture was stirred at 60° C. for 30 min and then treatedwith water. The precipitated product was collected by filtration, washedwith water and air dried. The solid was then dissolved in TFA and thesolution was stirred at 60° C. for 10 min. After cooling the solutionwas concentrated and the crude residue was dissolved in THF (1 mL), MeOH(1 mL), and aq. NH₄OH (1 mL). The mixture was stirred at 60° C. for 30min in a sealed container. The mixture was cooled, concentrated undervacuum and the crude product was diluted with CH₃CN and purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₉H₂₅D2FN₇O₃ (M+H)⁺: m/z=542.2; Found: 542.4. ¹H NMR(500 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.28 (d, J=5.0 Hz, 1H), 8.97 (s,1H), 8.82 (d, J=5.0 Hz, 1H), 8.29 (d, J=8.4 Hz, 1H), 8.18 (d, J=5.0 Hz,1H), 7.99 (d, J=5.0 Hz, 1H), 7.96-7.84 (m, 3H), 7.67 (s, 1H), 7.56 (td,J=8.4, 6.8 Hz, 1H), 7.47 (dd, J=8.4, 2.0 Hz, 1H), 7.06 (d, J=8.5 Hz,1H), 7.00 (t, J=8.8 Hz, 1H), 4.96 (s, 1H), 3.83 (dd, J=8.6, 5.3 Hz, 1H),3.78 (s, 3H), 3.74-3.65 (m, 1H), 3.38-3.35 (m, 1H), 3.32-3.29 (m, 1H),2.38 (dt, J=13.2, 7.8 Hz, 1H), 1.84 (dt, J=13.3, 5.4 Hz, 1H) ppm.

Example 56.N-(4-(4-Cyanopyridin-3-yl)-2-((1S,3R,4S)-3-(hydroxymethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 50, using (1S,4S,6R)-tert-butyl6-(hydroxymethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (preparedby an adaptation of the procedure described in: Balog, A. et al. Bioorg.Med. Chem. Lett. 2004, 14, 6107-6111) instead of (2R,5S)-tert-butyl5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate as starting material.LCMS calculated for C₃₀H₂₇FN₇O₃ (M+H)⁺: m/z=552.2; Found: 552.2.

Example 57.N-(4-(4-Cyanopyridin-3-yl)-2-((1S,4S)-1-(hydroxymethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 50, using (1S,4S)-tert-butyl4-(hydroxymethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (preparedby an adaptation of the procedure described in: Ivon, Y. et al.Synthesis 2015, 47, 1123-1130) instead of (2R,5S)-tert-butyl5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate as starting material.LCMS calculated for C₃₀H₂₇FN₇O₃ (M+H)⁺: m/z=552.2; Found: 552.3.

Example 58.N-(2-((2s,4S)-4-Amino-2-methylpiperidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. 2-((2S,4S)-2-Methylpiperidin-4-yl)isoindoline-1,3-dione

A solution of (2S,4R)-tert-butyl4-hydroxy-2-methylpiperidine-1-carboxylate (75 mg, 0.35 mmol),phthalimide (62 mg, 0.43 mmoL), and triphenylphosphine (111 mg, 0.43mmol) in THF (1.7 mL) was treated with DIAD (83 μL, 0.43 mmol) and themixture was stirred for 1 h at room temperature. The reaction mixturewas diluted with MeOH and EtOAc, washed with brine, dried over MgSO₄,filtered and the solvent was concentrated. The crude product was thentreated with HCl (4M in dioxane, 1 mL) and stirred for 1 h at roomtemperature. The solvent was concentrated under vacuum and the crudeproduct was used in the next reaction without purification. LCMScalculated for C₁₄H₁₇N₂O₂ (M+H)⁺: m/z=245.1; found 245.1.

Step 2.3-(3-((2S,4S)-4-(1,3-Dioxoisoindolin-2-yl)-2-methylpiperidin-1-yl)-4-nitrophenyl)isonicotinonitrile

A solution of 3-(3-fluoro-4-nitrophenyl)isonicotinonitrile (Intermediate1, 85 mg, 0.35 mmol) and2-((2S,4S)-2-methylpiperidin-4-yl)isoindoline-1,3-dione (85 mg, 0.35mmol) in DMSO (1.2 mL) was treated with triethylamine (73 μL, 0.52 mmol)and the reaction mixture was heated to 100° C. for 16 h. After coolingto room temperature, the reaction mixture was diluted with CH₂Cl₂,washed with brine, dried over MgSO₄, filtered and the solventconcentrated under vacuum. The crude product was used in the nextreaction without purification. LCMS calculated for C₂₆H₂₂N₅O₄ (M+H)⁺:m/z=468.2; found 468.1.

Step 3.3-(4-Amino-3-((2S,4S)-4-(1,3-dioxoisoindolin-2-yl)-2-methylpiperidin-1-yl)phenyl)isonicotinonitrile

A mixture of3-(3-((2S,4S)-4-(1,3-dioxoisoindolin-2-yl)-2-methylpiperidin-1-yl)-4-nitrophenyl)isonicotinonitrile(163 mg, 0.35 mmol), iron (97 mg, 1.70 mmol) and ammonium chloride (112mg, 2.10 mmol) in THF (2 mL), water (2 mL) and methanol (2 mL) wasstirred at 60° C. for 1 h. After cooling to room temperature, themixture was filtered through a plug of Celite and diluted with CH₂Cl₂.The organic phase was separated, washed with brine, dried over MgSO₄,filtered and the solvents were concentrated. The crude product was usedin the next step without further purification. LCMS calculated forC₂₆H₂₄N₅O₂ (M+H)⁺: m/z=438.2; Found: 438.1.

Step 4.N-(2-((2S,4S)-4-Amino-2-methylpiperidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

HATU (99 mg, 0.26 mmol) was added to a solution of3-(4-amino-3-((2S,4S)-4-(1,3-dioxoisoindolin-2-yl)-2-methylpiperidin-1-yl)phenyl)isonicotinonitrile(76 mg, 0.17 mmol), 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylicacid (43 mg, 0.17 mmol) and DIPEA (61 μL, 0.35 mmol) in DMF (400 μL).The reaction mixture was stirred at 60° C. for 30 min and then treatedwith water. The precipitated product was collected by filtration, washedwith water and air dried. The solid was then dissolved in EtOH (2 mL)and treated with hydrazine hydrate (aq. 50-60%, 1 mL). The solution wasstirred at 60° C. for 16 h, cooled and concentrated. The residue wasthen diluted with acetonitrile and purified with prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). LCMS calculated for C₃₀H₂₉FN₇O₂ (M+H)⁺:m/z=538.2; Found: 538.4.

Example 59.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-6-(2-fluoro-6-methoxyphenyl)picolinamide

Step 1. tert-Butyl(3S,5S)-1-(2-amino-5-(4-cyanopyridin-3-yl-phenyl)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate

This compound was prepared according to the procedures described inExample 50, Step 2, using tert-butyl(3S,5S)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate instead of(2R,5S)-tert-butyl 5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate asstarting material. LCMS calculated for C₂₂H₂₈N₅O₃ (M+H)⁺: m/z=410.2;Found: 410.1.

Step 2. tert-Butyl(3S,5S)-1-(2-(6-chloropicolinamido)-5-(4-cyanopyridin-3-yl)phenyl)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate

HATU (320 mg, 0.843 mmol) was added to a solution of tert-butyl((3S,5S)-1-(2-amino-5-(4-cyanopyridin-3-yl)phenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(230 mg, 0.562 mmol), 6-chloropicolinic acid (88 mg, 0.562 mmol) andDIPEA (0.196 ml, 1.123 mmol) in DMF (1 ml). After stirring at roomtemperature for 30 min, water (3 mL) was added. The desired product wascollected by filtration, washed with water and dried overnight. LCMScalculated for C₂₈H₃₀ClN₆O₄ (M+H)⁺: m/z=549.2; Found: 549.2.

Step 3.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-6-(2-fluoro-6-methoxyphenyl)picolinamid

A mixture of tert-butyl(3S,5S)-1-(2-(6-chloropicolinamido)-5-(4-cyanopyridin-3-yl)phenyl)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate(20 mg, 0.036 mmol), (2-fluoro-6-methoxyphenyl)boronic acid (6.20 mg,0.036 mmol), potassium phosphate, tribasic (15.49 mg, 0.073 mmol), XPhosPd G2 (3.03 mg, 3.65 μmol) in p-dioxane (1 mL) and water (0.2 mL) wasstirred at 70° C. for 2 h. The mixture was concentrated under vacuum anddissolved in DCM (1 mL) and TFA (1 mL). The resulting mixture wasstirred at room temperature for 15 min. The solvent was concentratedunder vacuum and the residue diluted with acetonitrile and purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₃₀H₂₈FN₆O₃ (M+H)⁺: m/z=539.2; Found: 539.1.

Example 60.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-5-cyano-6-(2-fluoro-6-methoxyphenyl)picolinamide

This compound was prepared according to the procedures described inExample 59, using 6-chloro-5-cyanopicolinic acid instead of6-chloropicolinic acid as starting material. LCMS calculated forC₃₁H₂₇FN₇O₃ (M+H)⁺: m/z=564.2; Found: 564.2.

Example 61.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-6-(2-fluoro-6-methoxyphenyl)-5-methoxypicolinamide

This compound was prepared according to the procedures described inExample 59, using 6-chloro-5-methoxypicolinic acid instead of6-chloropicolinic acid as starting material. LCMS calculated forC₃₁H₃₀FN₆O₄(M+H)⁺: m/z=569.2; Found: 569.2.

Example 62.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2,6-difluorophenyl)pyrimidine-4-carboxamide

Step 1. tert-Butyl(3S,5S)-1-(2-(2-chloropyrimidine-4-carboxamido)-5-(4-cyanopyridin-3-yl)phenyl)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate

This compound was prepared according to the procedures described inExample 59, Step 2, using 2-chloropyrimidine-4-carboxylic acid insteadof 6-chloropicolinic acid as starting material. LCMS calculated forC₂₇H₂₉ClN₇O₄ (M+H)⁺: m/z=550.2; Found: 550.1.

Step 2.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2,6-difluorophenyl)pyrimidine-4-carboxamide

A mixture of tert-butyl(3S,5S)-1-(2-(2-chloropyrimidine-4-carboxamido)-5-(4-cyanopyridin-3-yl)phenyl)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate(20 mg, 0.036 mmol), (2,6-difluorophenyl)boronic acid (5.75 mg, 0.036mmol), potassium phosphate, tribasic (15.46 mg, 0.073 mmol), XPhos Pd G2(3.02 mg, 3.64 μmol) in p-dioxane (1 mL) and water (0.2 mL) was stirredat 70° C. for 2 h. The mixture was concentrated under vacuum anddissolved in DCM (1 mL) and TFA (1 mL). The resulting mixture wasstirred at room temperature for 15 min and then the solvent wasconcentrated. The residue was diluted with acetonitrile and purifiedwith prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₈H₂₄F₂N₇O₂ (M+H)⁺: m/z=528.2; Found: 528.4.

Example 63.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methylphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 62, using (2-fluoro-6-methylphenyl)boronic acid instead of(2,6-difluorophenyl)boronic acid as starting material. LCMS calculatedfor C₂₉H₂₇FN₇O₂ (M+H)⁺: m/z=524.2; Found: 524.1.

Example 64.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-chloro-6-fluorophenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 62, using (2-chloro-6-fluorophenyl)boronic acid instead of(2,6-difluorophenyl)boronic acid as starting material. LCMS calculatedfor C₂₈H₂₄ClFN₇O₂ (M+H)⁺: m/z=544.2; Found: 544.2.

Example 65.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. tert-Butyl(3S,5S)-1-(6-bromo-3-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)pyridin-2-yl)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate

This compound was prepared according to the procedures described inExample 41 and 1, using 6-bromo-2-chloro-3-nitropyridine instead of4-bromo-2-fluoro-1-nitrobenzene as starting material. LCMS calculatedfor C₂₇H₃₁BrFN₆O₅ (M+H)⁺: m/z=617.2; Found: 617.2.

Step 2.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A mixture of tert-butyl(C₃S,5S)-1-(6-bromo-3-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)pyridin-2-yl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(35 mg, 0.057 mmol),1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.020 g, 0.085 mmol), Xphos Pd G2 (13 mg, 16 μmol) and potassiumphosphate, tribasic (67 mg, 0.32 mmol) was combined with 1,4-dioxane (1ml) and water (0.1 ml). The reaction flask was evacuated, back filledwith nitrogen, and then stirred at 80° C. for 1 h. The reaction mixturewas cooled to room temperature, the solvents were concentrated undervacuum, and TFA (1 ml) was added. The reaction mixture was stirred atroom temperature for 10 min, then diluted with CH₃CN and water, andpurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₈H₃₂FN₈O₃(M+H)⁺: m/z=547.3; Found: 547.3.

Example 66.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2,6-difluorophenyl)pyrimidine-4-carboxamide

Step 1. tert-Butyl((3S,5S)-1-(2-amino-4-fluorophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate

A solution of 1,4-difluoro-2-nitrobenzene (250 mg, 1.57 mmol) andtert-butyl ((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate (340 mg,1.57 mmol) in DMSO (5 ml) was treated with Hunig's base (274 μl, 1.57mmol) and the reaction mixture was heated to 90° C. for 1 hr. Thereaction mixture was treated with water and the product was extractedwith ethyl acetate. The organic phase was washed with water andsaturated aqueous sodium chloride, dried over sodium sulfate andconcentrated. The crude product was dissolved in a 1:1:1 mixture ofTHF/water/MeOH (9 mL) and treated with iron (351 mg, 6.29 mmol) andammonium chloride (504 mg, 9.43 mmol). The reaction mixture was heatedto 60° C. for 1 hr, then diluted with ethyl acetate and filtered througha plug of Celite. The filtrate was washed with water and saturatedaqueous sodium chloride, dried over sodium sulfate and concentrated. Thecrude product was purified by Biotage Isolera™ (30-100% ethyl acetate inhexanes) to provide the desired product as a yellow solid (226 mg, 46%).LCMS calculated for C₁₆H₂₅FN₃O₃ (M+H)⁺: m/z=326.2; Found: 326.2.

Step 2. tert-Butyl((3S,5S)-1-(2-(2-chloropyrimidine-4-carboxamido)-4-fluorophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate

A solution of 2-chloropyrimidine-4-carboxylic acid (87 mg, 0.550 mmol),HATU (230 mg, 0.605 mmol) and tert-butyl((3S,5S)-1-(2-amino-4-fluorophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(179 mg, 0.550 mmol) in DMF (1834 μl) was treated with Hunig's base (192μl, 1.100 mmol) and the reaction mixture was stirred at r.t. for 30mins, then treated with water and the product was extracted with ethylacetate. The organic phase was washed with water and brine, dried oversodium sulfate and concentrated. The crude product was purified byBiotage Isolera™ (25-100% ethyl acetate in hexane) to provide thedesired product (107 mg, 42%). LCMS calculated for C₂₁H₂₆ClFN₅O₄ (M+H)⁺:m/z=466.2; Found: 466.2.

Step 3.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2,6-difluorophenyl)pyrimidine-4-carboxamide

To a mixture of (2,6-difluorophenyl)boronic acid (15 mg, 0.097 mmol),XPhos Pd G2 (5.07 mg, 6.44 μmol), potassium phosphate (27.5 mg, 0.129mmol) and tert-butyl((3S,5S)-1-(2-(2-chloropyrimidine-4-carboxamido)-4-fluorophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(30 mg, 0.064 mmol) were added 1,4-dioxane (530 μl) and water (100 μl)and the flask was evacuated, back filled with nitrogen, then stirred at90° C. overnight. The reaction was diluted with DCM/water and the phasesseparated. The organic phase was concentrated and the residue wasdissolved in TFA (1 mL) and allowed to stand at r.t. for 30 mins, thendiluted with MeOH and purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₂H₂₁F₃N₅O₂ (M+H)⁺:m/z=444.2; Found: 444.2.

Example 67.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(3-cyano-2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared in an analogous fashion to Example 66, step3, using2-fluoro-4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrilein place of (2,6-difluorophenyl)boronic acid. LCMS calculated forC₂₄H₂₃F₂N₆O₃ (M+H)⁺: m/z=481.2; Found: 481.2.

Example 68.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2,3-difluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared in an analogous fashion to Example 66, step3, using (2,3-difluoro-6-methoxyphenyl)boronic acid in place of(2,6-difluorophenyl)boronic acid. LCMS calculated forC₂₃H₂₃F₃N₅O₃(M+H)⁺: m/z=474.2; Found: 474.2. ¹H NMR (500 MHz, DMSO-d6) δ10.69 (s, 1H), 9.30 (s, 1H), 8.21 (d, J=5.0 Hz, 1H), 8.18 (d, J=3.0 Hz,1H), 7.81 (s, 2H), 7.60 (q, J=9.5 Hz, 1H), 7.53 (dd, J=8.9, 5.8 Hz, 1H),7.13-6.96 (m, 2H), 5.19 (s, 1H), 3.75 (s, 4H), 3.56 (dd, J=8.2, 3.6 Hz,1H), 3.26-3.17 (m, 4H), 2.46-2.35 (m, 1H), 1.77 (dt, J=13.6, 4.1 Hz, 1H)ppm.

Example 69.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-(methoxy-d3)-3-methylphenyl)pyrimidine-4-carboxamide

Step 1. 2-Fluoro-4-(methoxy-d₃)-1-methylbenzene

A solution of 3-fluoro-4-methylphenol (1.0 g, 7.93 mmol) in DMF (26.4ml) was treated with potassium carbonate (1.644 g, 11.89 mmol) andiodomethane-d₃ (0.592 ml, 9.51 mmol) and the reaction mixture heated to80° C. for 1 hr. The reaction mixture was treated with water andextracted with diethyl ether. The organic phase was washed with waterand brine, dried over sodium sulfate and concentrated. The crude productwas used in the next step without further purification. LCMS calculatedfor C₈H₇D₃FO (M+H)⁺: m/z=144.2; Found: 144.2.

Step 2.2-(2-Fluoro-6-(methoxy-d₃)-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A solution of 2-fluoro-4-(methoxy-d₃)-1-methylbenzene (1.0 g, 6.98 mmol)and HMPA (1.823 ml, 10.48 mmol) in THF (34.9 ml) at −78° C. was treatedwith n-BuLi (2.5 M in hexanes, 3.35 ml, 8.38 mmol) dropwise and thereaction mixture stirred at this temperature for 1 hr.2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.166 ml, 10.48mmol) was then added and the reaction mixture stirred at −78° C. for 10mins, and then warmed up to r.t. by removing the cooling bath. Thereaction was treated with aqueous 1N HCl and extracted with ethylacetate. The organic phase was washed with water and brine, dried oversodium sulfate and concentrated. The crude product was used in the nextstep without further purification.

Step 3. Methyl2-(2-fluoro-6-(methoxy-d3)-3-methylphenyl)pyrimidine-4-carboxylic Acid

A solution of2-(2-fluoro-6-(methoxy-d₃)-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.56 g, 5.79 mmol) and Hunig's base (1 ml, 5.79 mmol) in water (1333μl) and 1,4-dioxane (12 mL) was treated with methyl2-chloropyrimidine-4-carboxylate (500 mg, 2.90 mmol) and ((t-Bu)₃P)₂Pd(74.0 mg, 0.145 mmol). The reaction flask was evacuated, back filledwith nitrogen, and stirred at 80° C. overnight. The reaction mixture wasthen diluted with DCM and filtered through a plug of Celite. Thefiltrate was concentrated and the residue purified by Biotage Isolera™(0-100% ethyl acetate in hexanes) to provide the desired intermediate.LCMS calculated for C₁₄H₁₁D₃FN₂O₃(M+H)⁺: m/z=280.2; Found: 280.2.

Step 4.2-(2-Fluoro-6-(methoxy-d₃)-3-methylphenyl)pyrimidine-4-carboxylic Acid

The product from the previous step was dissolved in a 1:1 mixture ofTHF/water (4 mL). Lithium hydroxide (238 mg, 5.79 mmol) was added andthe reaction mixture heated to 60° C. for 1 hr, then acidified to pH 1with 1 N HCl and extracted with ethyl acetate. The organic phase waswashed with brine, dried over sodium sulfate and concentrated. The crudeproduct was used in the next step without further purification. LCMScalculated for C₁₃H₉D₃FN₂O₃(M+H)⁺: m/z=266.2; Found: 266.2.

Step 5.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-(methoxy-d3)-3-methylphenyl)pyrimidine-4-carboxamide

A solution of2-(2-fluoro-6-(methoxy-d₃)-3-methylphenyl)pyrimidine-4-carboxylic acid(12.27 mg, 0.046 mmol), HATU (21.03 mg, 0.055 mmol) and tert-butyl((3S,5S)-1-(2-amino-4-fluorophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(Example 66, step 2; 15 mg, 0.046 mmol) in DMF (461 μl) was treated withHunig's base (16.10 μl, 0.092 mmol) and the reaction mixture stirred atr.t. for 30 mins. The reaction mixture was treated with water andextracted with ethyl acetate. The organic phase was washed with waterand brine, dried over sodium sulfate and concentrated. The crude productwas dissolved in TFA (1 mL), held at r.t. for 30 mins, then diluted withMeOH and purified with prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₂₄H₂₃D₃F₂N₅O₃ (M+H)⁺: m/z=473.2; Found:473.2.

Example 70.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxy-4-methylphenyl)pyrimidine-4-carboxamide

Step 1.2-(2-Fluoro-6-methoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

This compound was prepared in an analogous fashion to Example 69, step1-2 using 3-fluoro-5-methyl phenol instead of 3-fluoro-4-methylphenol.

Step 2. tert-Butyl((3S,5S)-1-(2-amino-5-bromophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate

A solution of 4-bromo-2-fluoro-1-nitrobenzene (1.0 g, 4.55 mmol) andtert-butyl ((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate (0.983 g,4.55 mmol) in DMF (15.15 ml) was treated with Hunig's base (1.588 ml,9.09 mmol) and the reaction mixture heated to 80° C. for 1 hr. Thereaction mixture was poured into water/ethyl acetate, the phasesseparated and the organic phase was washed with water and brine, driedover sodium sulfate and concentrated. The residue was dissolved in a1:1:1 mixture of THF/MeOH/water (15 mL) and treated with iron (1.015 g,18.18 mmol) and ammonium chloride (1.46 g, 27.3 mmol). The reactionmixture was heated to 60° C. overnight, then diluted with ethyl acetateand filtered through a plug of Celite. The filtrate was washed withwater and brine, dried over sodium sulfate and concentrated. The crudeproduct (1.61 g, 92%) was used in the next step without furtherpurification. LCMS calculated for C₁₆H₂₅BrN₃O₃(M+H)⁺: m/z=386.0/388.0;Found: 386.0/388.0.

Step 3. tert-Butyl((3S,5S)-1-(2-amino-5-(4-cyanopyridin-3-yl)phenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate

To a mixture of tert-butyl((3S,5S)-1-(2-amino-5-bromophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(200 mg, 0.518 mmol), XPhos Pd G2 (20.37 mg, 0.026 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isonicotinonitrile (155mg, 0.673 mmol) and potassium phosphate (220 mg, 1.035 mmol) was added1,4-dioxane (1438 μl) and water (288 μl) and the reaction flaskevacuated, back filled with nitrogen, then stirred at 90° C. for 1 hr.The mixture was diluted with ethyl acetate and filtered through a plugof Celite. The filtrate was concentrated and the residue was purified byBiotage Isolera™ (30-100% ethyl acetate in hexanes then 5-20% methanolin ethyl acetate) to provide the desired product as a brown solid (175mg, 83%). LCMS calculated for C₂₂H₂₈N₅O₃ (M+H)⁺: m/z=410.2; Found: 410.2

Step 4. tert-Butyl((3S,5S)-1-(2-(2-chloropyrimidine-4-carboxamido)-5-(4-cyanopyridin-3-yl)phenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate

A solution of 2-chloropyrimidine-4-carboxylic acid (119 mg, 0.751 mmol),HATU (314 mg, 0.826 mmol) and tert-butyl((3S,5S)-1-(2-amino-5-(4-cyanopyridin-3-yl)phenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(307 mg, 0.751 mmol) in DMF (3800 μl) was treated with Hunig's base (262μl, 1.502 mmol) and allowed to stir at r.t. for 30 mins. The reactionmixture was treated with water and extracted with ethyl acetate. Theorganic phase was washed with water and brine, dried over sodium sulfateand concentrated. The crude product was purified by Biotage Isolera™(40-100% ethyl acetate in hexanes) to provide the desired product as anorange solid (310 mg, 75%). LCMS calculated for C₂₇H₂₉ClN₇O₄ (M+H)⁺:m/z=550.2; Found: 550.2

Step 5.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxy-4-methylphenyl)pyrimidine-4-carboxamide

To a mixture of tert-butyl((3S,5S)-1-(2-(2-chloropyrimidine-4-carboxamido)-5-(4-cyanopyridin-3-yl)phenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(15 mg, 0.027 mmol),2-(2-fluoro-6-methoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(10.89 mg, 0.041 mmol), XPhos Pd G2 (2.145 mg, 2.73 μmol) and potassiumphosphate (12 mg, 0.055 mmol) were added water (54.5 μl) and 1,4-dioxane(218 μl) and the reaction flask was evacuated, back filled withnitrogen, then stirred at 90° C. overnight. The mixture was partitionedbetween DCM/water and the organic phase concentrated. The residue wasallowed to stand in TFA (1 mL) for 30 min, at r.t., then diluted withMeOH and purified with prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₃₀H₂₉F₂N₇O₃ (M+H)⁺: m/z=573.2; Found:573.2.

Example 71.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(3,6-difluoro-2-methylphenyl)pyrimidine-4-carboxamide

This compound was prepared in an analogous fashion to Example 70, step5, using (3,6-difluoro-2-methylphenyl)boronic acid in place of2-(2-fluoro-6-methoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.LCMS calculated for C₂₉H₂₆F₂N₇O₂ (M+H)⁺: m/z=542.2; Found: 542.2.

Example 72.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2,3-difluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared in an analogous fashion to Example 70, step5, using (2,3-difluoro-6-methoxyphenyl)boronic acid in place of2-(2-fluoro-6-methoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.LCMS calculated for C₂₉H₂₆F₂N₇O₃ (M+H)⁺: m/z=558.2; Found: 558.2.

Example 73.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(3,6-difluoro-2-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared in an analogous fashion to Example 70, step5, using (3,6-difluoro-2-methoxyphenyl)boronic acid in place of2-(2-fluoro-6-methoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.LCMS calculated for C₂₉H₂₆F₂N₇O₃ (M+H)⁺: m/z=558.2; Found: 558.2.

Example 74.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(3-cyano-2-fluoro-6-(methoxy-d₃)phenyl)pyrimidine-4-carboxamide

Step 1. 2-(3-Cyano-2-fluoro-6-(methoxy-d₃)phenyl)pyrimidine-4-carboxylicAcid

This compound was prepared in an analogous fashion to Example 69, steps1-4, starting with 3-fluoro-4-cyanophenol instead of3-fluoro-4-methylphenol. LCMS calculated for C₁₃H₆D₃FN₃O₃(M+H)⁺:m/z=277.2; Found: 277.2.

Step 2.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(3-cyano-2-fluoro-6-(methoxy-d3)phenyl)pyrimidine-4-carboxamide

A solution of2-(3-cyano-2-fluoro-6-(methoxy-d3)phenyl)pyrimidine-4-carboxylic acid(9.72 mg, 0.037 mmol), HATU (16.71 mg, 0.044 mmol) and tert-butyl((3S,5S)-1-(2-amino-5-(4-cyanopyridin-3-yl)phenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(Example 70, Step 4, 15 mg, 0.037 mmol) in DMF (366 μl) was treated withHunig's base (12.80 μl, 0.073 mmol) and the reaction mixture allowed tostir at r.t. for 30 mins. The reaction mixture was treated with waterand extracted with ethyl acetate. The organic phase was washed withwater and brine, dried over sodium sulfate and concentrated. The crudeproduct was dissolved in TFA (1 mL) and allowed to stand at r.t. for 30mins, then diluted with MeOH and purified with prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). LCMS calculated for C₃₀H₂₃D₃FN₈O₃(M+H)⁺: m/z=568.2; Found: 568.2.

Example 75.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(3,6-difluoro-2-(methoxy-d₃)phenyl)pyrimidine-4-carboxamide

Step 1. 2-(3,6-Difluoro-2-(methoxy-d₃)phenyl)pyrimidine-4-carboxylicacid

This compound was prepared in an analogous fashion to Example 69, steps1-4, starting with 2,5-difluorophenol instead of3-fluoro-4-methylphenol. LCMS calculated for C₁₂H₆D₃F₂N₂O₃ (M+H)⁺:m/z=270.2; Found: 270.2.

Step 2.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(3,6-difluoro-2-(methoxy-d3)phenyl)pyrimidine-4-carboxamide

This compound was prepared in an analogous fashion to Example 74, step2, using 2-(3,6-difluoro-2-(methoxy-d3)phenyl)pyrimidine-4-carboxylicacid as the coupling partner. LCMS calculated for C₂₉H₂₃D₃F₂N₇O₃ (M+H)⁺:m/z=561.2; Found: 561.2.

Example 76.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2,3-difluoro-6-(methoxy-d₃)phenyl)pyrimidine-4-carboxamide

This compound was prepared in an analogous fashion to Example 75, steps1-2 using 4,5-difluorophenol as starting material. LCMS calculated forC₂₉H₂₃D₃F₂N₇O₃ (M+H)⁺: m/z=561.2; Found: 561.2.

Example 77.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-(methoxy-d₃)phenyl-5-d)pyrimidine-4-carboxamide

Step 1. 1-Bromo-4-fluoro-2-(methoxy-d₃)benzene

A solution of 2-bromo-5-fluorophenol (1.0 g, 5.24 mmol) in DMF (17.45ml) was treated with potassium carbonate (1.085 g, 7.85 mmol) andiodomethane-d₃ (0.414 ml, 6.28 mmol). The reaction mixture was heated to60° C. overnight, then treated with water and extracted with ethylacetate. The organic phase was washed with water and brine, dried oversodium sulfate and concentrated. The crude product was used in the nextstep without further purification. LCMS calculated for C₇H₄D₃BrFO(M+H)⁺: m/z=208.0/210.0; Found: 208.0/210.0.

Step 2.2-(2-Fluoro-6-(methoxy-d₃)phenyl-5-d)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Magnesium (92 mg, 3.78 mmol) in THF (2 mL) was treated with iodine(23.97 mg, 0.094 mmol) followed by a solution of1-bromo-4-fluoro-2-(methoxy-d₃)benzene (393 mg, 1.889 mmol) in THF (8mL) dropwise. The mixture was heated to 60° C. for 1 hr, then thereaction mixture was cooled to r.t. and treated by the addition ofmethanol-d₄ (382 μl, 9.45 mmol). After stirring at r.t. for 15 mins, themixture was further treated with 1N HCl to destroy the remainingmagnesium. The mixture was then extracted with diethyl ether. Theorganic phase was washed with water and brine, dried over sodium sulfateand concentrated. To the crude intermediate was added THF (10 mL) andthe mixture cooled to −78° C. n-BuLi (1.6M in hexanes, 907 μl, 2.267mmol) was added dropwise and the reaction mixture stirred at −78° C. for1 hr. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (586 μl, 2.83mmol) was added. The mixture was stirred at −78° C. for 10 mins, thenwarmed to r.t. After 1 hr, the reaction was treated with saturatedaqueous ammonium chloride and extracted with ethyl acetate. The organicphase was washed with water and brine, dried over sodium sulfate andconcentrated. The crude product was used in the next step withoutfurther purification.

Step 3. N-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-(methoxy-d3)phenyl-5-d)pyrimidine-4-carboxamide

This compound was prepared in an analogous fashion to Example 70, step5, using the pinacol boronate prepared in Step 2 in place of2-(2-fluoro-6-methoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.LCMS calculated for C₂₉H₂₃D₄FN₇O₃ (M+H)⁺: m/z=544.2; Found: 544.2. ¹HNMR (600 MHz, DMSO-d6) δ 10.65 (s, 1H), 9.29 (d, J=5.0 Hz, 1H), 8.98 (s,1H), 8.83 (d, J=5.0 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.19 (d, J=5.0 Hz,1H), 7.99 (d, J=5.0 Hz, 1H), 7.93 (s, 2H), 7.68 (s, 1H), 7.60-7.53 (m,1H), 7.48 (d, J=9.9 Hz, 1H), 7.01 (t, J=8.8 Hz, 1H), 3.88-3.80 (m, 1H),3.73-3.68 (m, 1H), 3.41-3.29 (m, 3H), 3.26 (d, J=8.9 Hz, 1H), 2.39 (dt,J=15.7, 8.0 Hz, 1H), 1.86 (dt, J=11.2, 5.4 Hz, 1H) ppm.

Example 78.2-(2-Fluoro-6-methoxyphenyl)-N-(2-(piperidin-4-yl)phenyl)pyrimidine-4-carboxamide

Step 1. tert-Butyl 4-(2-aminophenyl)piperidine-1-carboxylate

To a mixture of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(230 mg, 0.743 mmol), 1-bromo-2-nitrobenzene (100 mg, 0.495 mmol), XPhosPd G2 (38.9 mg, 0.050 mmol) and potassium phosphate, tribasic (210 mg,0.990 mmol) were added 1,4-dioxane (1320 μl) and water (330 μl) and thereaction mixture evacuated, back filled with nitrogen, then heated to90° C. for 1 hr. The mixture was diluted with DCM and filtered through aplug of Celite. The filtrate was concentrated and the residue purifiedby Biotage Isolera™ (0-70% ethyl acetate in hexanes). To the purifiedproduct was added MeOH (4 mL) followed by palladium hydroxide on carbon(20% w/w, 69.5 mg, 0.099 mmol). The reaction flask was evacuated, backfilled with hydrogen gas from a ballon, then heated to 60° C. overnight.The mixture was then filtered through a plug of Celite and the filtrateconcentrated. The crude product (130 mg, 95%) was used in the next stepwithout further purification. LCMS calculated for C₁₆H₂₅N₂O₂(M+H)⁺:m/z=277.2; Found: 277.2.

Step 2.2-(2-Fluoro-6-methoxyphenyl)-N-(2-(piperidin-4-yl)phenyl)pyrimidine-4-carboxamide

A solution of 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid(93 mg, 0.376 mmol), HATU (215 mg, 0.564 mmol) and tert-butyl4-(2-aminophenyl)piperidine-1-carboxylate (130 mg, 0.470 mmol) in DMF(2352 μl) was treated with Hunig's base (164 μl, 0.941 mmol) and thereaction mixture was stirred at r.t. for 30 mins. The reaction mixturewas treated with water and extracted with ethyl acetate. The organicphase was washed with water and brine, dried over sodium sulfate andconcentrated. The residue was dissolved in TFA (1 mL) and allowed tostand for 30 mins, then diluted with methanol and purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₃H₂₄FN₄O₂ (M+H)⁺: m/z=407.2; Found: 407.2.

Example 79.N-(2-(cis)4-Aminocyclohexyl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide andN-(2-(trans)4-Aminocyclohexyl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

These compounds were prepared in an analogous fashion to Example 78,steps 1-2 starting with tert-butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)carbamate.Purification by prep-LCMS provided the cis and trans isomers. LCMScalculated for C₂₄H₂₆FN₄O₂ (M+H)⁺: m/z=421.2; Found: 421.2.

Example 80.N-(2-(3-Aminocyclohexyl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared in an analogous fashion to Example 78, steps1-2 starting with tert-butyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-yl)carbamate.LCMS calculated for C₂₄H₂₆FN₄O₂ (M+H)⁺: m/z=421.2; Found: 421.2.

Example 81.N-(2-(3-aminocyclopentyl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared in an analogous fashion to Example 78, steps1-2 starting with tert-butyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-3-en-1-yl)carbamate.LCMS calculated for C₂₃H₂₄FN₄O₂ (M+H)⁺: m/z=407.2; Found: 407.2.

Example 82.N-(2-((cis)-4-Aminocyclohexyl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideandN-(2-((trans)-4-Aminocyclohexyl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. tert-Butyl (4-(2-amino-5-hydroxyphenyl)cyclohexyl)carbamate

To a mixture of tert-butyl(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)cyclohex-3-en-1-yl)carbamate(308 mg, 0.947 mmol), 4-chloro-2-iodoaniline (200 mg, 0.789 mmol),DPPF-PdCl₂ (64.4 mg, 0.079 mmol) and potassium carbonate (218 mg, 1.578mmol) were added 1,4-dioxane (3156 μl) and water (789 μl). The reactionflask was evacuated, back filled with nitrogen, then stirred at 90° C.for 2 hr. The mixture was diluted with DCM and filtered through a plugof Celite. The filtrate was concentrated and the residue purified byBiotage Isolera™ (0-100% ethyl acetate in hexanes). The crude materialwas dissolved in EtOH (4 mL) and palladium hydroxide on carbon (20% w/w,111 mg, 0.158 mmol) was added. The reaction flask was evacuated, backfiled with hydrogen gas from a balloon, then stirred at 60° C. for 2 hr.The reaction mixture was then diluted with ethyl acetate and filteredthrough a plug of Celite. The filtrate was concentrated and the crudeproduct used in the next step without further purification. LCMScalculated for C₁₇H₂₇N₂O₃ (M+H)⁺: m/z=307.2; Found: 307.2.

Step 2.3-(4-((tert-Butoxycarbonyl)amino)cyclohexyl)-4-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl trifluoromethanesulfonate

A solution of 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid(64.0 mg, 0.258 mmol), HATU (118 mg, 0.309 mmol) and tert-butyl(4-(2-amino-5-hydroxyphenyl) cyclohexyl)carbamate (79 mg, 0.258 mmol) inDMF (1289 μl) was treated with Hunig's base (90 μl, 0.516 mmol) and thereaction mixture was stirred at r.t. for 30 mins. The reaction mixturewas diluted with water and extracted with ethyl acetate. The organicphase was washed with water and brine, dried over sodium sulfate andconcentrated. The crude product was purified by Biotage Isolera™(20-100% ethyl acetate in hexanes). The intermediate was dissolved inDCM (3 mL) and triethylamine (71.9 μl, 0.516 mmol) was added. Thereaction mixture was cooled to 0° C. andA-phenyltrifluoromethanesulfonimide (92 mg, 0.258 mmol) in DCM (0.5 mL)was added dropwise. The reaction mixture was then warmed to r.t. andstirred for 2 hr, and then treated with saturated sodium bicarbonate.The phases were separated and the organic phase dried over sodiumsulfate and concentrated. The crude product was purified by BiotageIsolera™ (20-100% ethyl acetate in hexanes) to provide the desiredproduct as a white solid (68 mg, 40%). LCMS calculated for C₃₀H₃₃F₄N₄O₇S(M+H)⁺: m/z=669.2; Found: 669.2.

Step 3.N-(2-((cis)-4-Aminocyclohexyl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideandN-(2-((trans)-4-aminocyclohexyl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

To a solution of3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isonicotinonitrile (35.1mg, 0.153 mmol), DPPF-PdCl₂ (8.30 mg, 10.17 μmol), cesium carbonate(66.3 mg, 0.203 mmol) and3-(4-((tert-butoxycarbonyl)amino)cyclohexyl)-4-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyltrifluoromethanesulfonate (68 mg, 0.102 mmol) was added 1,4-dioxane (915μl) and water (102 μl) and the reaction flask was evacuated, back filledwith nitrogen, then heated to 90° C. overnight. The mixture was thendiluted with water and DCM and the phases separated. The organic phasewas concentrated. The residue was allowed to stand in TFA (1 mL) for 30mins at r.t., then diluted with MeOH and purified with prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). The two isomers weresuccessfully separated by prep-LCMS. LCMS calculated for C₃₀H₂₈FN₆O₂(M+H)⁺: m/z=523.2; Found: 523.2.

Example 83.N-(2-((cis)-4-Aminocyclohexyl)-4-(4-cyano-1-methyl-1H-pyrazol-5-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideandN-(2-((trans)-4-aminocyclohexyl)-4-(4-cyano-1-methyl-1H-pyrazol-5-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared in an analogous fashion to Example 82, step 2using1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-4-carbonitrileas coupling partner. LCMS calculated for C₂₉H₂₉FN₇O₂ (M+H)⁺: m/z=526.2;Found: 526.2.

Example 84.N-(2-((c/s)-4-Aminocyclohexyl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared in an analogous fashion to Example 82, step 2using1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleas coupling partner. LCMS calculated for C₃₀H₃₄FN₆O₂ (M+H)⁺: m/z=529.2;Found: 529.2. ¹H NMR (500 MHz, DMSO-d6) δ 10.42 (s, 1H), 9.25 (d, J=5.0Hz, 1H), 8.13 (d, J=5.0 Hz, 1H), 7.75 (s, 2H), 7.54 (q, J=8.1 Hz, 1H),7.47 (d, J=8.1 Hz, 1H), 7.20 (s, 1H), 7.15 (d, J=8.2 Hz, 1H), 7.07 (d,J=8.5 Hz, 3H), 7.01 (t, J=8.8 Hz, 1H), 3.80 (s, 3H), 3.71 (s, 3H), 3.08(s, 1H), 2.64 (t, J=11.9 Hz, 1H), 2.25 (s, 3H), 2.16 (s, 3H), 1.98 (d,J=11.6 Hz, 2H), 1.87 (d, J=12.3 Hz, 2H), 1.56 (q, J=12.5 Hz, 2H), 1.30(q, J=12.0, 11.4 Hz, 2H) ppm.

Example 85.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(methylsulfonyl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. tert-Butyl((3S,5S)-1-(2-amino-5-(methylsulfonyl)phenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate

A mixture of 2-fluoro-4-(methylsulfonyl)-1-nitrobenzene (100 mg, 0.456mmol) and tert-butyl ((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(118 mg, 0.547 mmol) in DMSO (1521 μl) was treated with Hunig's base(159 μl, 0.912 mmol) and the reaction mixture stirred at 90° C. for 1hr, then treated with water and extracted with ethyl acetate. Theorganic phase was washed with water and brine, dried over sodium sulfateand concentrated. The residue was dissolved in a 1:1:1 mixture ofTHF/water/MeOH (3 mL) and treated with iron (102 mg, 1.825 mmol) andammonium chloride (146 mg, 2.74 mmol). The reaction mixture was stirredat 60° C. for 1 hr, then diluted with ethyl acetate and filtered througha plug of Celite. The filtrate was washed with water and brine, driedover sodium sulfate and concentrated. The crude solid was used in thenext step without further purification. LCMS calculated for C₁₇H₂₈N₃O₅S(M+H)⁺: m/z=386.2; Found: 386.2.

Step 2.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(methylsulfonyl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A solution of tert-butyl((3S,5S)-1-(2-amino-5-(methylsulfonyl)phenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate (55 mg, 0.143 mmol) in DMF (476 μl) wastreated with 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid(31.9 mg, 0.128 mmol), HATU (65.1 mg, 0.171 mmol), and Hunig's base(49.8 μl, 0.285 mmol). The reaction mixture was stirred at r.t. for 30mins, then treated with water and extracted with ethyl acetate. Theorganic phase was washed with water and brine, dried over sodium sulfateand concentrated. To the crude residue was added 4N HCl in dioxane andMeOH (2 mL, 1:1) and the reaction mixture heated to 60° C. for 1 hr,then diluted with MeOH and purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₄H₂₇FN₅O₅S (M+H)⁺:m/z=516.2; Found: 516.2.

Example 86.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. tert-Butyl((3S,5S)-5-(hydroxymethyl)-1-(2-nitrophenyl)pyrrolidin-3-yl)carbamate

A solution of 1-fluoro-2-nitrobenzene (30 μl, 0.283 mmol) and tert-butyl((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate (61.3 mg, 0.283mmol) in DMSO (1.5 ml) was treated with triethylamine (59.3 μl, 0.425mmol) and the reaction mixture was heated to 80° C. for 3 hrs. Aftercooling to r.t., the reaction mixture was diluted with DCM, washed withbrine, dried over sodium sulfate and the solvent was evaporated invacuo. The obtained crude product was used in the next step withoutfurther purification. LCMS calculated for C₁₂H₁₆N₃O₅(M+H—C₄H₈)⁺:m/z=282.1; found 282.2.

Step 2. tert-Butyl((3S,5S)-1-(2-aminophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate

A mixture of tert-butyl((3S,5S)-5-(hydroxymethyl)-1-(2-nitrophenyl)pyrrolidin-3-yl)carbamate(70 mg, 0.207 mmol), iron (57.9 mg, 1.037 mmol) and ammonium chloride(67 mg, 1.25 mmol) in THF (2 ml), water (2 ml) and methanol (2 ml) wasstirred at 60° C. for 3 hrs. After cooling to r.t., it was filteredthrough a plug of Celite and diluted with DCM. The organic phase wasseparated, washed with brine, dried over sodium sulfate and the solventswere evaporated in vacuo. The obtained crude product was used in thenext step without further purification. LCMS calculated for C₁₆H₂₆N₃O₃(M+H)⁺: m/z=308.2; Found: 308.2.

Step 3.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

HATU (74.2 mg, 0.195 mmol) was added to a solution of tert-butyl((3S,5S)-1-(2-aminophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(40 mg, 0.130 mmol), 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylicacid (the product of Example 1, step 1, 32.3 mg, 0.130 mmol) and DIPEA(45.5 μl, 0.260 mmol) in DMF (1 ml). The reaction mixture was stirred atr.t. for 30 mins, then water was added and the precipitated product wascollected by filtration, washed with water and air dried. The solid wasdissolved in TFA and the resultant solution was stirred at r.t. for 10mins. It was then diluted with acetonitrile and purified with prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated forC₂₃H₂₅FN₅O₃ (M+H)⁺: m/z=438.2; Found: 438.2. ¹H NMR (500 MHz, DMSO-d6) δ10.61-10.48 (s, 1H), 9.34-9.19 (d, J=5.0 Hz, 1H), 8.21-8.11 (m, 2H),7.95-7.80 (br, 2H), 7.60-7.49 (td, J=8.4, 6.8 Hz, 1H), 7.41-7.33 (dd,J=6.7, 2.5 Hz, 1H), 7.25-7.15 (m, 2H), 7.11-7.03 (d, J=8.5 Hz, 1H),7.03-6.93 (t, J=8.8 Hz, 1H), 3.79-3.74 (s, 3H), 3.75-3.62 (m, 2H),3.37-3.16 (m, 4H), 2.43-2.31 (m, 1H), 1.87-1.74 (dt, J=13.4, 5.1 Hz, 1H)ppm.

Example 87.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-methylphenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 6, using 1-fluoro-4-methyl-2-nitrobenzene instead of1,4-difluoro-2-nitrobenzene as starting material. LCMS calculated forC₂₄H₂₇FN₅O₃ (M+H)⁺: m/z=452.2; Found: 452.2.

Example 88.N-(2-((2S,4S)-4-(Dimethylamino)-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Sodium triacetoxyborohydride (9 mg, 0.044 mmol) was added to a solutionof formaldehyde (1.4 mg, 0.044 mmol), acetic acid (2.51 μl, 0.044 mmol)andN-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide(Example 6, 10 mg, 0.022 mmol) in DCM (1 ml). After stirring at r.t. for1h, the solvent was evaporated, the reaction mixture was diluted withCH₃CN and purified with prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₂₅H₂₈F₂N₅O₃ (M+H)⁺: m/z=484.2; Found:484.2.

Example 89.N-(5-Fluoro-2-((2S,4S)-2-(hydroxymethyl)-4-(isopropylamino)pyrrolidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 88, using acetone instead of formaldehyde as starting material.LCMS calculated for C₂₆H₃₀F₂N₅O₃ (M+H)⁺: m/z=498.2; Found: 498.1.

Example 90.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(tetrahydro-2H-pyran-4-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 49, using2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane asstarting material. LCMS calculated for C₂₈H₃₃FN₅O₄ (M+H)⁺: m/z=522.2;Found: 522.2.

Example 91.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-chlorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 6, using 4-chloro-2-fluoro-1-nitrobenzene instead of1,4-difluoro-2-nitrobenzene as starting material. LCMS calculated forC₂₃H₃₃FN₅O₃ (M+H)⁺: m/z=472.2; Found: 472.3.

Example 92.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 6, using 2,4-difluoro-1-nitrobenzene instead of1,4-difluoro-2-nitrobenzene as starting material. LCMS calculated forC₂₃H₂₄F₂N₅O₃ (M+H)⁺: m/z=456.2; Found: 456.3.

Example 93.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(5-cyano-2-(pyrrolidin-1-yl)pyridin-4-yl)phenyl)-2-(2,6-difluorophenyl)pyrimidine-4-carboxamide

Step 1. 4-Bromo-6-(pyrrolidin-1-yl)nicotinonitrile

A solution of 4-bromo-6-chloronicotinonitrile (200 mg, 0.920 mmol) andpyrrolidine (327 mg, 4.60 mmol) in 2-propanol (2 mL) was stirred at 100°C. for 12 h. Then the solvent was evaporated in vacuo. The obtainedcrude product was used in the next step without further purification.LCMS calculated for C₁₀H₁₁BrN₃ (M+H)⁺: m/z=252.0; Found: 252.0.

Step 2. tert-Butyl((3S,5S)-1-(2-(2-(2,6-difluorophenyl)pyrimidine-4-carboxamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate

This compound was prepared according to the procedures described inExample 46 and 41 using (2,6-difluorophenyl)boronic acid instead of(2-fluoro-6-methoxyphenyl)boronic acid as starting material. LCMScalculated for C₃₃H₄₁BF₂N₅O₆ (M+H)⁺: m/z=652.3; Found: 652.2.

Step 3.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(5-cyano-2-(pyrrolidin-1-yl)pyridin-4-yl)phenyl)-2-(2,6-difluorophenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 46, Step 2, using 4-bromo-6-(pyrrolidin-1-yl)nicotinonitrileinstead of 2-bromonicotinonitrile and tert-butyl((3S,5S)-1-(2-(2-(2,6-difluorophenyl)pyrimidine-4-carboxamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamateinstead of tert-butyl((3S,5S)-1-(2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamateas starting material. LCMS calculated for C₃₂H₃₁F₂N₈O₂ (M+H)⁺:m/z=597.3; Found: 597.2.

Example 94.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(1-cyanocyclopropyl)phenyl)-2-(2,6-difluorophenyl)pyrimidine-4-carboxamide

Step 1. tert-Butyl((3S,5S)-1-(5-(cyanomethyl)-2-nitrophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate

This compound was prepared according to the procedures described inExample 6, using 2-(3-fluoro-4-nitrophenyl)acetonitrile instead of1,4-difluoro-2-nitrobenzene as starting material. LCMS calculated forC₁₄H₁₇N₄O₅ (M-C₄H₈+H)⁺: m/z=321.1; Found: 321.1.

Step 2. tert-Butyl((3S,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-(5-(cyanomethyl)-2-nitrophenyl)pyrrolidin-3-yl)carbamate

tert-Butylchlorodimethylsilane (0.054 g, 0.359 mmol) was added to asolution of 1H-imidazole (0.024 g, 0.359 mmol) and tert-butyl((3S,5S)-1-(5-(cyanomethyl)-2-nitrophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(0.090 g, 0.239 mmol) in 1 mL of DCM. After the reaction mixture wasstirred at r.t. for 2 h, water was added and product was extracted withDCM. The combined organic phases were washed with water and brine, driedover sodium sulfate and the solvent was evaporated in vacuo. Theobtained crude product was used in the next step without furtherpurification. LCMS calculated for C₂₀H₃₁N₄O₅Si (M-C₄H₈+H)⁺: m/z=435.2;Found: 435.2.

Step 3. tert-Butyl((3S,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-(5-(1-cyanocyclopropyl)-2-nitrophenyl)pyrrolidin-3-yl)carbamate

A solution of tert-Butyl((3S,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-(5-(cyanomethyl)-2-nitrophenyl)pyrrolidin-3-yl)carbamate(0.120 g, 0.245 mmol) in 1 mL of DMF was treated with 1,2-dibromoethane(0.046 g, 0.245 mmol). The mixture was stirred at r.t. and then treatedwith sodium hydride (0.120 g, 5.00 mmol). The mixture was furtherstirred at r.t. overnight. Then water was added and precipitated productwas collected by filtration, washed with water and air dried. It wasused in the next step without further purification. LCMS calculated forC₂₂H₃₃N₄O₅Si (M-C₄H₈+H)⁺: m/z=461.2; Found: 461.2.

Step 4.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(I-cyanocyclopropyl)phenyl)-2-(2,6-difluorophenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 1, using (2,6-difluorophenyl)boronic acid instead of(2-fluoro-6-methoxyphenyl)boronic acid and tert-butyl((3S,5S)-5-(((tert-butyl dimethylsilyl)oxy)methyl)-1-(5-(1-cyanocyclopropyl)-2-nitrophenyl)pyrrolidin-3-yl)carbamateinstead of (1R,4R)-tert-butyl5-(4-fluoro-2-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylateas starting material. LCMS calculated for C₂₆H₂₅F₂N₆O₂ (M+H)⁺:m/z=491.2; Found: 491.1.

Example 95.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-(difluoromethoxy)-6-fluorophenyl)pyrimidine-4-carboxamide

Step 1. 2-Bromo-1-(difluoromethoxy)-3-fluorobenzene

A mixture of 2-bromo-3-fluorophenol (0.865 g, 4.53 mmol), sodiumchlorodifluoroacetate (4.14 g, 27.2 mmol) and cesium carbonate (4.43 g,13.59 mmol) in DMF (10 mL) was stirred at 100° C. for 4 h. After coolingto room temperature, the mixture was concentrated in vacuo. The obtainedcrude product was purified by Biotage Isolera™ to give the desiredproduct.

Step 2.2-(2-(Difluoromethoxy)-6-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A solution of 2-bromo-1-(difluoromethoxy)-3-fluorobenzene (400 mg, 1.660mmol) in THF (10 mL) was treated with nBuLi 1.6 M (1.72 mL, 4.32 mmol)at −78° C. After stirring for 1 h,2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.02 mL, 4.98mmol) was added, and then the mixture was slowly warmed to rt over 6 h.To the mixture was added EtOAc (50 mL) and water (30 mL). The organicphase was separated, washed with brine, dried over MgSO₄, filtered andthe solvents were evaporated in vacuo. The obtained crude product wasused in the next step without further purification.

Step 3.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-(difluoromethoxy)-6-fluorophenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 63, using2-(2-(difluoromethoxy)-6-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of (2,6-difluorophenyl)boronic acid as starting material. LCMScalculated for C₂₉H₂₅F₃N₇O₃ (M+H)⁺: m/z=576.2; Found: 576.3.

Example 96.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-(methoxy-d₃)phenyl)pyrimidine-4-carboxamide

Step 1.2-(2-Fluoro-6-(methoxy-d3)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

This compound was prepared in an analogous fashion to Example 69,starting with 3-fluorophenol instead of 3-fluoro-4-methylphenol. LCMScalculated for C₁₅H₁₆D₃BFC₃(M+H)⁺: m/z=256.2; Found: 256.2.

Step 2.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-(methoxy-d3)phenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 63, using2-(2-fluoro-6-(methoxy-d₃)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of (2,6-difluorophenyl)boronic acid as starting material. LCMScalculated for C₂₉H₂₄D₃FN₇O₃ (M+H)⁺: m/z=543.2; Found: 543.3.

Example 97.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-cyclopropyl-6-fluorophenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 63, using2-(2-cyclopropyl-6-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of (2,6-difluorophenyl)boronic acid as starting material. LCMScalculated for C₃₁H₂₉FN₇O₂ (M+H)⁺: m/z=550.2; Found: 550.3.

Example 98.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-ethoxy-6-fluorophenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 63, using (2-ethoxy-6-fluorophenyl)boronic acid instead of(2,6-difluorophenyl)boronic acid as starting material. LCMS calculatedfor C₃₀H₂₉FN₇O₃ (M+H)⁺: m/z=554.2; Found: 554.3.

Example 99.N-(4-(4-Cyanopyridin-3-yl)-2-((1S,4S)-4-(hydroxymethyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. tert-Butyl(1S,4S)-4-(hydroxymethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

A Parr reaction vessel were charged with tert-butyl(1S,4S)-4-(hydroxymethyl)-5-(4-methoxybenzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(prepared by an adaption of the procedure described in Ivon, Y. et. al.Synthesis 2015, 47, 1123-1130) (25 mg, 0.072 mmol), Pd/C (10% wetted,Degussa type, 7.7 mg) followed by MeOH (7.2 mL) and the reaction mixturewas evacuated and backfilled 3 times with nitrogen gas, followed byanother evacuation cycle and then pressurized with hydrogen gas to 25psi. The vessel was shook for 6 hrs under hydrogen pressure, upon whichtime the solution was filtered over Celite and the solvent wasevaporated in vacuo. The obtained crude product was used in the nextreaction without purification. LCMS calculated for C₁₁H₂₁N₂C₃(M+H)⁺:m/z=229.2; found 229.2.

Step 2. tert-Butyl(1S,4S)-4-(hydroxymethyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

A solution of tert-butyl(1S,4S)-4-(hydroxymethyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate(16.5 mg, 0.072 mmol) in CH₃CN (200 μL) and H₂O (50 μL) were treatedwith formaldehyde (37 wt. % in H₂O, 16.1 μL, 0.217 mmol) and sodiumtriacetoxyborohydride (31 mg, 0.145 mmol) and the reaction mixture wasstirred at r.t. for 2 hrs. The reaction mixture was then diluted withCH₂Cl₂, washed with sat. aq. NaHCO₃, dried over MgSO₄, filtered and thesolvent was evaporated in vacuo. The obtained crude product was used inthe next reaction without purification. LCMS calculated forC₁₂H₂₃N₂O₃(M+H)⁺: m/z=243.2; found 243.2.

Step 3.3-(3-(1S,4S)-4-(Hydroxymethyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-nitrophenyl)isonicotinonitrile

A mixture of tert-butyl(1S,4S)-4-(hydroxymethyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(17 mg, 0.070 mmol) and 4M HCl/dioxane (1 mL) was stirred at r.t. for 1hr before the solvent was evaporated in vacuo. The residue was thentreated with 3-(3-fluoro-4-nitrophenyl)isonicotinonitrile (Intermediate1 described between Example 49 and 50, 17.1 mg, 0.070 mmol), DMSO (300μL), triethylamine (14.7 μL, 0.943 mmol) and the reaction mixture washeated to 100° C. overnight. After cooling to r.t., the reaction mixturewas diluted with DCM, washed with brine, dried over sodium sulfate andthe solvent was evaporated in vacuo. The obtained crude product was usedin the next step without further purification. LCMS calculated forC₁₉H₂₀N₅O₃(M+H)⁺: m/z=366.2; found 366.1.

Step 4.3-(4-Amino-3-(#1S,4S)-4-(hydroxymethyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)isonicotinonitrile

A mixture of3-(3-((1S,4S)-4-(hydroxymethyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-nitrophenyl)isonicotinonitrile(26 mg, 0.071 mmol), iron (20.0 mg, 0.356 mmol) and ammonium chloride(22.9 mg, 0.427 mmol) in THF (1 mL), H₂O (1 mL) and methanol (1 mL) wasstirred at 60° C. for 1 hr. After cooling to r.t., it was filteredthrough a plug of Celite and diluted with CH₂Cl₂. The organic phase wasseparated, washed with brine, dried over MgSO₄, filtered and thesolvents were evaporated in vacuo. The obtained crude product was usedin the next step without further purification. LCMS calculated forC₁₉H₂₂N₅O (M+H)⁺: m/z=336.2; Found: 336.2.

Step 5.N-(4-(4-Cyanopyridin-3-yl)-2-(1S,4S)-4-(hydroxymethyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

HATU (20.4 mg, 0.054 mmol) was added to a solution of3-(4-amino-3-((1S,4S)-4-(hydroxymethyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)isonicotinonitrile(13 mg, 0.036 mmol), 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylicacid (8.9 mg, 0.036 mmol) and DIPEA (12.5 μL, 0.072 mmol) in DMF (300μL). The reaction mixture was stirred at 60° C. for 30 min, then waterwas added and the precipitated product was collected by filtration,washed with water and air dried. The solid was dissolved in TFA and theresultant solution was stirred at 60° C. for 10 min before solvent wasevaporated in vacuo. The crude residue was then dissolved in THF (1 mL),MeOH (1 mL), and aq. NH₄OH (1 mL), sealed and the solution was stirredat 60° C. for 30 min before solvent was evaporated in vacuo. Theobtained crude product was then diluted with CH₃CN and purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₃₁H₂₉FN₇O₃ (M+H)⁺: m/z=566.2; Found: 566.2.

Example 100.(S)—N-(4-(4-Cyanopyridin-3-yl)-2-(2-(hydroxymethyl)morpholino)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 51, using (S)-morpholin-2-yl methanol instead of(2S,5S)-tert-butyl 5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate asstarting material. LCMS calculated for C₂₉H₂₆FN₆O₄ (M+H)⁺: m/z=541.2;Found: 541.3.

Example 101.(S)—N-(4-(4-Cyanopyridin-3-yl)-2-(2-((dimethylamino)methyl)morpholino)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1.(R)—N-(4-(4-Cyanopyridin-3-yl)-2-(2-(hydroxymethyl)morpholino)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared in an analogous fashion to Example 51, steps1-3, starting with (R)-morpholin-2-ylmethanol instead of(2R,5S)-tert-butyl 5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate asstarting material. LCMS calculated for C₂₉H₂₆FN₆O₄ (M+H)⁺: m/z=541.2;Found: 541.3.

Step 2.(R)-(4-(5-(4-Cyanopyridin-3-yl)-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)morpholin-2-yl)methyl4-methylbenzenesulfonate

A solution of(R)—N-(4-(4-cyanopyridin-3-yl)-2-(2-(hydroxymethyl)morpholino)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide(100 mg, 0.185 mmol) in CH₂Cl₂ (740 μL) was treated with DMAP (2.3 mg,0.018 mmol), triethylamine (77 μL, 0.555 mmol), and TsCl (42.3 mg, 0.222mmol) and the reaction mixture was stirred at r.t. overnight. Thereaction mixture was then diluted with EtOAc, washed with 10% aq. citricacid, sat. aq. NaHCO₃, dried over MgSO₄, filtered and the solvent wasevaporated in vacuo. The obtained crude product was used in the nextreaction without purification. LCMS calculated for C₃₆H₃₂FN₆O₆S (M+H)⁺:m/z=695.2; found 695.3.

Step 3.(S)—N-(4-(4-Cyanopyridin-3-yl)-2-(2-((dimethylamino)methyl)morpholino)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A solution of(R)-(4-(5-(4-cyanopyridin-3-yl)-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)morpholin-2-yl)methyl4-methylbenzenesulfonate (20 mg, 0.029 mmol) in EtOH (480 μL) wastreated with dimethylamine (461 μL, 0.921 mmol). The reaction mixturewas stirred at 100° C. overnight. The solvent was evaporated in vacuo,and the resulting residue was diluted with acetonitrile and purifiedwith prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).C₃₁H₃₁FN₇O₃ (M+H)⁺: m/z=568.2; found 568.3.

Example 102.(R)—N-(2-(2-(Cyanomethyl)morpholino)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A solution of(R)-(4-(5-(4-cyanopyridin-3-yl)-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)morpholin-2-yl)methyl4-methylbenzenesulfonate (20 mg, 0.029 mmol) in EtOH (480 μL) wastreated with potassium cyanide (5.6 mg, 0.086 mmol). The reactionmixture was stirred at 100° C. for 6 hrs. The solvent was evaporated invacuo, and the resulting residue was diluted with acetonitrile andpurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).C₃₀H₂₅FN₇O₃ (M+H)⁺: m/z=550.2; found 550.2.

Example 103.(R)—N-(4-(4-Cyanopyridin-3-yl)-2-(3-oxotetrahydro-3H-oxazolo[3,4-a]pyrazin-7(1H)-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. tert-Butyl(R)-4-(5-(4-cyanopyridin-3-yl)-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)-2-(hydroxymethyl)piperazine-1-carboxylate

This compound was prepared in an analogous fashion to Example 51, steps1-3, starting with tert-butyl(R)-2-(hydroxymethyl)piperazine-1-carboxylate instead of(2S,5S)-tert-butyl 5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate asstarting material. LCMS calculated for C₃₄H₃₅FN₇O₅ (M+H)⁺: m/z=640.3;Found: 640.2.

Step 2. tert-Butyl(R)-4-(5-(4-cyanopyridin-3-yl)-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)-2-(((methylsulfonyl)oxy)methyl)piperazine-1-carboxylate

A solution of tert-butyl(R)-4-(5-(4-cyanopyridin-3-yl)-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)-2-(hydroxymethyl)piperazine-1-carboxylate(30 mg, 0.047 mmol) in CH₂Cl₂ (470 μL) was treated with triethylamine(13.1 μL, 0.094 mmol), and MsCl (5.5 μL, 0.070 mmol) and the reactionmixture was stirred at r.t. for 1 hr. The solvent was evaporated invacuo. The obtained crude product was used in the next reaction withoutpurification. LCMS calculated for C₃₅H₃₇FN₇O₇S (M+H)⁺: m/z=718.2; found718.2.

Step 3.(R)—N-(4-(4-Cyanopyridin-3-yl)-2-(3-oxotetrahydro-3H-oxazolo[3,4-a]pyrazin-7(1H)-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Potassium cyanide (9.2 mg, 0.142 mmol) was added to a solution oftert-butyl(R)-4-(5-(4-cyanopyridin-3-yl)-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)-2-(((methylsulfonyl)oxy)methyl)piperazine-1-carboxylate(34 mg, 0.047 mmol) in DMSO (475 μL). The reaction mixture was stirredat 80° C. for 1 hr. After cooling to r.t., the resulting solution wasdiluted with acetonitrile and purified with prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). C₃₀H₂₅FN₇O₄ (M+H)⁺: m/z=566.2; found566.3.

Example 104.(S)—N-(5-Fluoro-2-(3-(hydroxymethyl)piperazin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared in an analogous fashion to Example 6,starting with tert-butyl (S)-2-(hydroxymethyl)piperazine-1-carboxylatein place of tert-butyl(3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate as starting material.LCMS calculated for C₂₃H₂₄F₂N₅O₃ (M+H)⁺: m/z=456.2; Found: 456.3. ¹H NMR(400 MHz, DMSO) δ 11.03-10.69 (s, 1H), 9.48-9.26 (d, J=5.0 Hz, 1H),8.38-8.21 (dd, J=10.8, 3.0 Hz, 1H), 8.20-8.09 (d, J=5.0 Hz, 1H),7.68-7.51 (td, J=8.4, 6.9 Hz, 1H), 7.42-7.31 (dd, J=8.8, 5.6 Hz, 1H),7.13-6.96 (m, 3H), 3.83-3.71 (s, 3H), 3.59-3.18 (m, 6H), 3.15-2.79 (m,4H), 2.81-2.69 (s, 1H).

Example 105.N-(4-(4-Cyanopyridin-3-yl)-2-(3-(methoxymethyl)azetidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared in an analogous fashion to Example 51,starting with 3-(methoxymethyl)azetidine in place of (2R,5S)-tert-butyl5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate as starting material.LCMS calculated for C₂₉H₂₆FN₆O₃ (M+H)⁺: m/z=525.2; Found: 525.2.

Example 106.(S)—N-(4-(4-Cyanopyridin-3-yl)-2-(2-(hydroxymethyl)azetidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared in an analogous fashion to Example 51,starting with (S)-azetidin-2-ylmethanol in place of (2S,5S)-tert-butyl5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate as starting material.LCMS calculated for C₂₈H₂₄FN₆O₃ (M+H)⁺: m/z=511.2; Found: 511.2.

Example 107.(R)—N-(4-(4-Cyanopyridin-3-yl)-2-(2-((dimethylamino)methyl)azetidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1.(R)—N-(4-(4-Cyanopyridin-3-yl)-2-(2-(hydroxymethyl)azetidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared in an analogous fashion to Example 51,starting with (R)-azetidin-2-ylmethanol in place of (2S,5S)-tert-butyl5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate as starting material.LCMS calculated for C₂₈H₂₄FN₆O₃(M+H)⁺: m/z=511.2; Found: 511.2.

Step 2.(R)-(1-(5-(4-Cyanopyridin-3-yl)-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)azetidin-2-yl)methylmethane sulfonate

A solution of(S)—N-(4-(4-cyanopyridin-3-yl)-2-(2-(hydroxymethyl)azetidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide(50 mg, 0.098 mmol) in CH₂Cl₂ (980 μL) was treated with triethylamine(27 μL, 0.196 mmol), and MsCl (11.4 μL, 0.147 mmol) and the reactionmixture was stirred at r.t. for 2 hrs. The solvent was evaporated invacuo. The obtained crude product was used in the next reaction withoutpurification. LCMS calculated for C₂₉H₂₆FN₆O₅S (M+H)⁺: m/z=589.2; found589.3.

Step 3.(R)—N-(4-(4-Cyanopyridin-3-yl)-2-(2-((dimethylamino)methyl)azetidin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A solution of(R)-(1-(5-(4-cyanopyridin-3-yl)-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)azetidin-2-yl)methylmethanesulfonate (20 mg, 0.034 mmol) in EtOH (570 μL) was treated withdimethylamine (544 μL, 1.09 mmol). The reaction mixture was stirred at100° C. overnight. After cooling to r.t., the solvent was evaporated invacuo, and the resulting residue was diluted with acetonitrile andpurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).C₃₀H₂₉FN₇O₂ (M+H)⁺: m/z=538.2; found 538.2.

Example 108.N-(4-(4-Cyanopyridin-3-yl)-2-(4-methylpiperazin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1.N-(4-(4-Cyanopyridin-3-yl)-2-(piperazin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared in an analogous fashion to Example 51,starting with tert-butyl piperazine-1-carboxylate in place of(2S,5S)-tert-butyl 5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate asstarting material. LCMS calculated for C₂₈H₂₅FN₇O₂ (M+H)⁺: m/z=510.2;Found: 510.2.

Step 2.N-(4-(4-Cyanopyridin-3-yl)-2-(4-methylpiperazin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A solution ofN-(4-(4-cyanopyridin-3-yl)-2-(piperazin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide(15 mg, 0.029 mmol) in THF (980 μL) was treated with formaldehyde (37wt. % in H₂O, 110 μL, 1.47 mmol), acetic acid (8.4 μL, 0.147 mmol), andsodium triacetoxyborohydride (12.5 mg, 0.059 mmol) and the reactionmixture was stirred at r.t. for 1 h. The solvent was then evaporated invacuo, and the resulting residue was diluted with acetonitrile andpurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).C₂₉H₂₇FN₇O₂ (M+H)⁺: m/z=524.2; found 524.2.

Example 109.N-(4-(4-Cyanopyridin-3-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A solution ofN-(4-(4-cyanopyridin-3-yl)-2-(piperazin-1-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide(15 mg, 0.029 mmol) in THF (980 μL) was treated with2-((tert-butyldimethylsilyl)oxy)acetaldehyde (34 μL, 0.177 mmol), aceticacid (5.0 μL, 0.088 mmol), and sodium triacetoxyborohydride (12.5 mg,0.059 mmol) and the reaction mixture was stirred at r.t. for 1 h. Uponcompletion, 4M HCl/dioxane (1 mL) was added and the reaction was left tostir for 30 min. The solvent was then evaporated in vacuo and theresulting residue was diluted with acetonitrile and purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).C₃₀H₂₉FN₇O₃ (M+H)⁺: m/z=554.2; found 554.4.

Example 110.(S)—N-(5-Fluoro-2-(3-(hydroxymethyl)piperazin-1-yl)-4-isopropylphenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. tert-Butyl(S)-4-(5-chloro-4-fluoro-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)-2-(hydroxymethyl)piperazine-1-carboxylate

This compound was prepared according to the procedures described inExample 41, using 1-chloro-2,5-difluoro-4-nitrobenzene in place of3-(3-fluoro-4-nitrophenyl)isonicotinonitrile as starting material. LCMScalculated for C₂₈H₃₁ClF₂N₅O₅ (M+H)⁺: m/z=590.2; Found: 590.2.

Step 2. tert-Butyl(S)-4-(4-fluoro-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-5-(prop-1-en-2-yl)phenyl)-2-(hydroxymethyl)piperazine-1-carboxylate

To a mixture of tert-butyl(S)-4-(5-chloro-4-fluoro-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)-2-(hydroxymethyl)piperazine-1-carboxylate(20 mg, 0.034 mmol),4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (9.6 μL,0.051 mmol), Xphos Pd G2 (2.7 mg, 3.4 μmol) and potassium phosphate,tribasic (14.4 mg, 0.068 mmol) were added 1,4-dioxane (500 μL) and H₂O(100 μL) and the reaction flask was evacuated, back filled withnitrogen, then stirred at 80° C. for 1 hr. The reaction mixture wascooled to r.t., the solvents were evaporated in vacuo and the crudeproduct was purified by Biotage Isolera™ (0-100% ethyl acetate inhexanes) to provide the desired product. LCMS calculated forC₃₁H₃₆F₂N₅O₅ (M+H)⁺: m/z=596.3; Found: 596.3.

Step 3.(S)—N-(5-Fluoro-2-(3-(hydroxymethyl)piperazin-1-yl)-4-isopropylphenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Palladium on carbon (10% wetted, Degussa type, 3.6 mg) was added to asolution of tert-butyl(S)-4-(4-fluoro-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-5-(prop-1-en-2-yl)phenyl)-2-(hydroxymethyl)piperazine-1-carboxylate(20 mg, 0.034 mmol) in methanol (1.1 ml). The reaction flask wasconnected to a balloon with hydrogen and the reaction mixture wasstirred at r.t. for 2 hrs. The catalyst was then filtered off, thesolvent was evaporated in vacuo and TFA (2 mL) was added. The reactionmixture was stirred at r.t. for 15 min, then diluted with CH₃CN andwater and purified with prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₂₆H₃₀F₂N₅O₃ (M+H)⁺: m/z=498.2; Found:498.3.

Example A. HPK1 Kinase Binding Assay

A stock solution of 1 mM test compound was prepared in DMSO. Thecompound plate was prepared by 3-fold and 11-point serial dilutions. 0.1μL of the compound in DMSO was transferred from the compound plate tothe white 384 well polystyrene plates. The assay buffer contained 50 mMHEPES, pH 7.5, 0.01% Tween-20, 5 mM MgCl₂, 0.01% BSA, and 5 mM DTT. 5 μLof 4 nM active HPK1 (SignalChem M23-11G) prepared in the buffer wasadded to the plate. The enzyme concentration given was based on thegiven stock concentration reported by the vender. 5 μl of 18 nM tracer222 (ThermoFisher PV6121) and 4 nM LanthaScreen Eu-Anti GST antibody(ThermoFisher PV5595) were added. After one hour incubation at 25° C.,the plates were read on a PHERAstar FS plate reader (BMG Labtech). Kivalues were determined.

Compounds of the present disclosure, as exemplified in Examples, showedthe K_(i) values in the following ranges: +=Ki≤100 nM; ++=100 nM<Ki≤500nM; +++=500 nM<Ki≤5000 nM.

TABLE 1 Example Ki, nM 1 + 2 + 3 + 4 + 5 ++ 6 + 7 + 8 +++ 9 +++ 10 +11 + 12 + 13 + 14 + 15 + 16 + 17 + 18 + 19 + 20 + 21 + 22 + 23 + 24 +25 + 26 + 27 + 28 + 29 + 30 + 31 + 32 + 33 + 34 + 35 + 36 + 37 ++ 38 +39 + 40 + 41 + 42 + 43 + 44 + 45 + 46 + 47 + 48 + 49 + 50 + 51 + 52 +53 + 54 + 55 + 56 + 57 + 58 + 59 + 60 + 61 ++ 62 + 63 + 64 + 65 + 66 +67 + 68 + 69 + 70 + 71 + 72 + 73 + 74 + 75 + 76 + 77 + 78 ++ 79, peak1 + 79, peak 2 + 80 + 81 + 82, peak 1 + 82, peak 2 + 83, peak 1 + 83,peak 2 + 84 + 85 + 86 + 87 + 88 + 89 + 90 + 91 + 92 + 93 + 94 + 95 +96 + 97 + 98 + 99 + 100 + 101 + 102 + 103 + 104 + 105 + 106 + 107 +108 + 109 + 110 +

Example B. p-SLP76S376 HTRF Assay

One or more compounds of the invention can be tested using thep-SLP76S376 HTRF assay described as follows. Jurkat cells (cultured inRPMI1640 media with 10% FBS) are collected and centrifuged, followed byresuspension in appropriate media at 3×10⁶ cells/mL.

The Jurkat cells (35 μL) are dispensed into each well in a 384 wellplate. Test compounds are diluted with cell culture media for 40-folddilution (adding 39 μL cell culture media into 1 μL compound). TheJurkat cells in the well plate are treated with the test compounds atvarious concentrations (adding 5 ul diluted compound into 35 μL Jurkatcells and starting from 3 uM with 1:3 dilution) for 1 hour at 37° C. 5%CO₂), followed by treatment with anti-CD3 (5 μg/mL, OKT3 clone) for 30min. A 1:25 dilution of 100× blocking reagent (from p-SLP76 ser376HTRFkit) with 4×Lysis Buffer (LB) is prepared and 15 μL of the 4×LB bufferwith blocking reagent is added into each well and incubated at roomtemperature for 45 min with gentle shaking. The cell lysate (16 μL) isadded into a Greiner white plate, treated with p-SLP76 ser376HTRFreagents (2 μL donor, 2 ul acceptor) and incubated at 4° C. forovernight. The homogeneous time resolved fluorescence (HTRF) is measuredon a PHERAstar plate reader the next day. IC₅₀ determination isperformed by fitting the curve of percent inhibition versus the log ofthe inhibitor concentration using the GraphPad Prism 5.0 software.

Example C. Isolation of CD4+ or CD8+ T Cells and Cytokine Measurement

Blood samples are collected from healthy donors. CD4+ or CD8+ T cellsare isolated by negative selection using CD4+ or CD8+ enrichment kits(lifetech, USA). The purity of the isolated CD4+ or CD8+ T cells isdetermined by flow cytometry and is routinely >80%. Cells are culturedin RPMI 1640 supplemented with 10% FCS, glutamine and antibiotics(Invitrogen Life Technologies, USA). For cytokine measurement, Jurkatcells or primary CD4+ or CD8+ T cells are plated at 200 k cells/well andare stimulated for 24 h with anti-CD3/anti-CD28 beads in the presence orabsence of testing compounds at various concentrations. 16 μL ofsupernatants are then transferred to a white detection plate andanalyzed using the human IL2 or IFNγ assay kits (Cisbio).

Example D. Treg Assay

One or more compounds can be tested using the Regulatory T-cellproliferation assay described as following. Primary CD4+/CD25− T-cellsand CD4+/CD25+ regulatory T-cells are isolated from human donatedPeripheral Blood Mononuclear Cells, using an isolated kit from ThermoFisher Scientific (11363D). CD4+/CD25− T-cells are labeled with CFSE(Thermo Fisher Scientific, C34554) following the protocol provided bythe vendor. CFSE labeled T-cells and CD4+/CD25+ regulatory T-cells arere-suspended at the concentration of 1×106 cells/mL in RPMI-1640 medium.100 μL of CFSE-labeled T-cells are mixed with or without 50 μL ofCD4+/CD25+ aregulatory T-cells, treated with 5 μl of anti-CD3/CD28 beads(Thermo Fisher Scientific, 11132D) and various concentrations ofcompounds diluted in 50 μl of RPMI-1640 medium. Mixed populations ofcells are cultured for 5 days (37° C. 5% CO₂) and proliferation ofCFSE-labeled T-cells is analyzed by BD LSRFortessa X-20 using FITCchannel on the 5th day.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including withoutlimitation all patent, patent applications, and publications, cited inthe present application is incorporated herein by reference in itsentirety.

What is claimed is:
 1. A method for treating a cancer in a patient, saidmethod comprising: administering to the patient a therapeuticallyeffective amount of a compound selected from:N-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;andN-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide,or a pharmaceutically acceptable salt of any of the aforementioned;wherein the cancer is selected from breast cancer, colorectal cancer,lung cancer, ovarian cancer, pancreatic cancer, Burkitt's lymphoma,acute promonocytic leukemia, and hepatocellular carcinoma.
 2. The methodof claim 1, wherein the cancer is selected from breast cancer,colorectal cancer, lung cancer, ovarian cancer, and pancreatic cancer.3. The method of claim 1, wherein the cancer is breast cancer.
 4. Themethod of claim 1, wherein the cancer is colorectal cancer.
 5. Themethod of claim 1, wherein the cancer is lung cancer.
 6. The method ofclaim 1, wherein the cancer is ovarian cancer.
 7. The method of claim 1,wherein the cancer is pancreatic cancer.
 8. The method of claim 1,wherein the cancer is Burkitt's lymphoma.
 9. The method of claim 1,wherein the cancer is acute promonocytic leukemia.
 10. The method ofclaim 1, wherein the compound isN-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide,or a pharmaceutically acceptable salt thereof.
 11. The method of claim1, wherein the compound isN-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide.12. The method of claim 2, wherein the compound isN-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide,or a pharmaceutically acceptable salt thereof.
 13. The method of claim8, wherein the compound isN-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide,or a pharmaceutically acceptable salt thereof.
 14. The method of claim9, wherein the compound isN-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide,or a pharmaceutically acceptable salt thereof.
 15. The method of claim1, wherein the compound isN-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide,or a pharmaceutically acceptable salt thereof.
 16. The method of claim1, wherein the compound isN-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide.17. The method of claim 2, wherein the compound isN-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide,or a pharmaceutically acceptable salt thereof.
 18. The method of claim8, wherein the compound isN-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide,or a pharmaceutically acceptable salt thereof.
 19. The method of claim9, wherein the compound isN-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide,or a pharmaceutically acceptable salt thereof.
 20. The method of claim1, wherein the compound isN-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide,or a pharmaceutically acceptable salt thereof.
 21. The method of claim1, wherein the compound isN-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide.22. The method of claim 2, wherein the compound isN-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide,or a pharmaceutically acceptable salt thereof.
 23. The method of claim8, wherein the compound isN-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide,or a pharmaceutically acceptable salt thereof.
 24. The method of claim9, wherein the compound isN-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide,or a pharmaceutically acceptable salt thereof.
 25. The method of claim1, wherein the cancer is hepatocellular carcinoma.